Risk for gastric neoplasias in patients with chronic atrophic gastritis:A critical reappraisal

Chronic atrophic gastritis (CAG) is an inflammatory condition characterized by the loss of gastric glandular structures which are replaced by connective tissue (non-metaplastic atrophy) or by glandular structures inappropriate for location (metaplastic atrophy).Epidemiological data suggest that CAG is associated with two different types of tumors:Intestinal-type gastric cancer (GC) and type Ⅰ gastric carcinoid (TⅠGC).The pathophysiological mechanisms which lead to the development of these gastric tumors are different.It is accepted that a multistep process initiating from Helicobacter pylori-related chronic inflammation of the gastric mucosa progresses to CAG,intestinal metaplasia,dysplasia and,finally,leads to the development of GC.The TⅠGC is a gastrin-dependent tumor and the chronic elevation of gastrin,which is associated with CAG,stimulates the growth of enterochromaffin-like cells with their hyperplasia leading to the development of TⅠGC.Thus,several events occur in the gastric mucosa before the development of intestinal-type GC and/or TⅠGC and these take several years.Knowledge of CAG incidence from superficial gastritis,its prevalence in different clinical settings and possible risk factors associated with the progression of this condition to gastric neoplasias are important issues.This editorial intends to provide a brief review of the main studies regarding incidence and prevalence of CAG and risk factors for the development of gastric neoplasias.

Magnified and enhanced computed virtual chromoendoscopy in gastric neoplasia: A feasibility study

AIM: To evaluate the feasibility of a new computed virtual chromoendoscopy (CVC) device (M i-scan) in the diagnosis of gastric neoplasia. METHODS: Patients with superficial lesions no larger than 1.0 cm found during high definition endoscopy were included. Those with advanced or obviously protruded or depressed lesions, lesions larger than 1.0 cm and/or lesions which were not amenable to observation by zoom function were excluded. The endoscopist was required to give the real-time descriptions of surface pit patterns of the lesions, based on surface pattern classification of enhanced magnification endoscopy. According to previous reports, types Ⅰ-Ⅲ represent nonneoplastic lesions, and types Ⅳ-Ⅴ represent neoplastic lesions. Diagnosis with M i-scan and biopsy was performed before histopathological diagnosis. Magnified images of gastric lesions with and without enhancement were collected for further analysis. The diagnostic yield of real-time M i-scan and effects on magnification image quality by tone enhancement (TE), surface enhancement (SE) and color enhancement (CE) were calculated. The selected images were sent to another endoscopist. The endoscopist rated the image quality of each lesion at 3 levels. Ratings of image quality were based on visualization of pit pattern, vessel and demarcation line. RESULTS: One hundred and eighty-three patients were recruited. Five patients were excluded for advanced gastric lesions, 1 patient was excluded for poor preparation and 2 patients were excluded for superficial lesions larger than 1.0 cm; 132 patients were excluded for no lesions found by high definition endoscopy. In the end, 43 patients with 43 lesions were included. Histopathology revealed 10 inflammation, 14 atrophy, 10 metaplasia, 1 low grade dysplasia (LGD), 5 high grade dysplasia (HGD) and 3 cancers. For 7 lesions classified into type Ⅰ, histopathology revealed 6 atrophy and 1 metaplasia; for 10 lesions classified into type Ⅱ, histopathology revealed 2 inflammation, 7 atrophy and 1 metaplasia; for 10 lesions classified into type Ⅲ, histopathology revealed 1 inflammation, 8 metaplasia and 1 LGD; for 9 lesions classified into type Ⅳ, histopathology revealed 4 inflammation, 1 atrophy and 4 HGD; for 7 lesions classified into type Ⅴ, histopathology revealed 3 inflammation, 1 HGD and 3 cancers. A total of 172 still images, including 43 images by white light (MWL) and 129 images by M i-scan (43 with TE, 43 with SE and 43 with CE), were selected and sent to the endoscopist who did the analysis. General image quality of M i-scan with TE and SE was significantly better than that of MWL (TE, 4.55 ± 1.07; SE, 4.30 ± 1.02; MWL, 3.25 ± 0.99; P < 0.001). Visualization of pit pattern was significantly improved by M i-scan with SE (1.93 ± 0.25 vs 1.50 ± 0.50, P < 0.001). Microvessel visualization was significantly improved by M i-scan with TE (1.23 ± 0.78 vs 0.76 ± 0.73, P < 0.001). Demarcation line visualization was improved by M i-scan with both TE and SE (TE, 1.75 ± 0.52; SE, 1.56 ± 0.59; MWL, 0.98 ± 0.44; P < 0.001). M i-scan with CE did not show any significant improvements of image quality in general or in the 3 key parameters. Although M i-scan with TE and SE slightly increased the diagnostic yield of MWL, there was no significant difference (P > 0.1). CONCLUSION: Although digital enhancement improves the image quality of magnification endoscopy, its value in improving the diagnostic yield seems to be limited.

Surveillance using trimodal imaging endoscopy after endoscopic submucosal dissection for superficial gastric neoplasia

AIM:To evaluate the effectiveness of trimodal imaging endoscopy(TME)to detect another lesion afterendoscopic submucosal dissection(ESD)for superficial gastric neoplasia(SGN).METHODS:Surveillance esophagogastroduodenoscopy(EGD)using a TME was conducted in 182 patients that had undergone ESD for SGN.Autofluorescence imaging(AFI)was conducted after white-light imaging(WLI).When SGN was suspicious,magnifying endoscopy with narrow-band imaging(ME-NBI)was conducted.Final diagnoses were made by histopathologic findings of biopsy specimens.The detection rates of lesions in WLI,AFI,and NBI,and the characteristics of lesions detected by WLI and ones missed by WLI but detected by AFI were examined.The sensitivity,specificity,and accuracy of endoscopic diagnosis using WLI,AFI and ME-NBI were evaluated.RESULTS:In 242 surveillance EGDs,27 lesions were determined pathologically to be neoplasias.Sixteen early gastric cancers and 6 gastric adenomas could be detected by WLI.Sixteen lesions were reddish and 6were whitish.Five gastric neoplasias were missed by WLI but were detected by AFI,and all were whitish and protruded gastric adenomas.There was a significant difference in color and pathology between the two groups(P=0.006).Sensitivity,specificity and accuracy in MENBI were higher than those in both WLI and AFI.Specificity and accuracy in AFI were lower than those in WLI.CONCLUSION:Surveillance using trimodal imaging endoscopy might be useful for detecting another lesion after endoscopic submucosal dissection for superficial gastric neoplasia.

Characteristics of early gastric tumors with different differentiation and predictors of long-term outcomes after endoscopic submucosal dissection

BACKGROUND Gastric cancer is a common malignant tumor of the digestive tract,and endosco-pic submucosal dissection(ESD)is the preferred treatment for early-stage gastric cancer.The analysis of the epidemiological characteristics of gastric mucosal tumors with different differentiation degrees and the influencing factors of long-term ESD efficacy may have certain significance for revealing the development of gastric cancer and ESD.AIM To analyze the features of gastric mucosal tumors at different differentiation levels,and to explore the prognostic factors of ESD.METHODS We retrospectively studied 301 lesions in 285 patients at The Second Affiliated Hospital of Xi'an Jiaotong University from 2014 to 2021,according to the latest Japanese guidelines(sixth edition),and divided them into low-grade intrae-pithelial neoplasia(LGIN),high-grade intraepithelial neoplasia(HGIN),and computed tomography at 3,6 and 12 months after ESD.We compared clinicopathologic characteristics,ESD efficacy,and complications with different degrees of differentiation,and analyzed the related factors associated with ESD.RESULTS HGIN and differentiated carcinoma patients were significantly older compared with LGIN patients(P<0.001)and accounted for more 0-IIc(P<0.001),atrophic gastritis was common(P<0.001),and irregular microvascular patterns(IMVPs)and demarcation lines(DLs)were more obvious(P<0.001).There was more infiltration in the undifferentiated carcinoma tissue(P<0.001),more abnormal folds and poorer mucosal peristalsis(P<0.001),and more obvious IMVPs,irregular microsurface patterns and DLs(P<0.05)than in the LGIN and HGIN tissues.The disease-free survival rates at 2,5,and 8 years after ESD were 95.0%,90.1%,and 86.9%,respectively.Undifferen-tiated lesions(HR 5.066),white moss(HR 7.187),incomplete resection(HR 3.658),and multiple primary cancers(HR 2.462)were significantly associated with poor prognosis.CONCLUSION Differentiations of gastric mucosal tumors have different epidemiological and endoscopic characteristics,which are closely related to the safety and efficacy of ESD.

Gene mutations in stool from gastric and colorectal neoplasia patients by next-generation sequencing

AIM To study cancer hotspot mutations by next-generation sequencing(NGS) in stool DNA from patients with different gastrointestinal tract(GIT) neoplasms. METHODS Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by usingthe PSP~? Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliS eq Cancer Hotspot Panel v2 or Ion AmpliS eq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis.RESULTS NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC,CDKN2 A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS,NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations.APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions.CONCLUSION Our results show that in addition to colorectal neoplasms,mutations can also be assayed from stool specimens of patients with gastric neoplasms.

Diagnosis of gastric intraepithelial neoplasia by narrow-band imaging and confocal laser endomicroscopy

AIM:To evaluate the diagnosis of different differentiated gastric intraepithelial neoplasia (IN) by magnifica-tion endoscopy combined with narrow-band imaging (ME-NBI) and confocal laser endomicroscopy (CLE). METHODS:Eligible patients with suspected gastric IN lesions previously diagnosed by endoscopy in secondary hospitals and scheduled for further diagnosis and tratment were recruited for this study. Excluded from the study were patients who had liver cirrhosis, impaired renal function, acute gastrointestinal (GI) bleeding, coagulopathy, esophageal varices, jaundice, and GI post-surgery. Also excluded were those who were pregnant, breastfeeding, were younger than 18 years old, or were unable to provide informed consent. All patients had all mucus and bile cleared from their stom-achs. They then received upper GI endoscopy. When a mucosal lesion is found during observation with whitelight imaging, the lesion is visualized using maximal magnification, employing gradual movement of the tip of the endoscope to bring the image into focus. Saved images are analyzed. Confocal images were evaluated by two endoscopists (Huang J and Li MY), who were familiar with CLE, blinded to the related information about the lesions, and asked to classify each lesion as either a low grade dysplasia (LGD) or high grade dysplasia (HGD) according to given criteria. The results were compared with the final histopathologic diagnosis. ME-NBI images were evaluated by two endoscopists (Lu ZS and Ling-Hu EQ) who were familiar with NBI, blinded to the related information about the lesions and CLE images, and were asked to classify each lesion as a LGD or HGD according to the "microvascular pattern and surface pattern" classification system. The results were compared with the final histopathologic diagnosis. RESULTS: The study included 32 pathology-proven low grade gastric IN and 26 pathology-proven high grade gastric IN that were detected with any of the modalities. CLE and ME-NBI enabled clear visualization of the vascular microsurface patterns and microvascular structures of the gastric mucosa. The accuracy of the CLE and the ME-NBI diagnosis was 88% (95% CI:78%-98%) and 81% (95% CI: 69%-93%), respectively. The kappa coefficient of agreement between the histopathology and the in vivo CLE imaging was 0.755; between the histopathology and the in vivo CLE imaging was 0.615. McNemar's test (binomial distribution used) indicated that the agreement was significant (P < 0.05). When patients were diagnosed by MENBI with CLE, the overall accuracy of the diagnosis was 86.21% (95% CI:73%-96%), and the kappa coefficient of agreement was 0.713, according to McNemar's test (P < 0.05). CONCLUSION:Higher diagnostic accuracy, sensitivityand specificity of CLE over ME-NBI indicate the feasibility of these two techniques for the efficacious diagnostic classification of gastric IN.

Predictive factors of endoscopic submucosal dissection procedure time for gastric superficial neoplasia

AIM:To identify the determinants of endoscopic submucosal dissection(ESD) operation time.METHODS:This investigation was conducted as a single-center,prospective study in which ESD was performed by the same endoscopist at the Chinese PLA General Hospital.A total of 173 patients underwent ESD operations performed by Dr.Lu from July 2007 to December 2011,and 183 lesions were enrolled.Patient gender,age,tumor location,gross type,tumor size,pathological type and adhesions were recorded prospectively.The order of treatment represented the experience of the operator.Univariate analysis and multivariate analysis were performed to evaluate the relationships between these factors and ESD procedure time.RESULTS:Univariate analysis showed the ESD time was closely related to the gender(P = 0.0210),tumor size(P < 0.0001),location(P < 0.0001),gross type(P < 0.0001) and adhesion(P = 0.0010).The surgical proficiency level was associated with ESD time in unit area(P < 0.0001).Multivariate analysis revealed that the ESD time was positively correlated with tumor size(P < 0.0001),adhesion(P < 0.0001) and location(P < 0.0001),but negatively correlated with surgical proficiency level(P = 0.0046).CONCLUSION:Large tumor size,adjacency to the cardia,and adhesion are predictors of a long ESD time,whereas high surgical proficiency level predicts a short ESD time.

Diagnosis and therapies for gastric non-invasive neoplasia

There has been a great discrepancy of pathological diagnosis for gastric non-invasive neoplasia/dysplasia between Japanese and western pathologists. In Japan, lesions that most western pathologists diagnose as dysplasia are often considered adenocarcinoma based on nuclear and structural atypia regardless of the presence of invasion. In the Vienna classification, gastric non-invasive intraepithelial neoplasia(NIN) weredivided into low grade and high grade(including intramucosal cancer of Japanese criteria). The diagnosis by both endoscopy and pathology of biopsy specimen is difficult. Recent advances of diagnostic modality such as magnified endoscopy and imaged enhanced endoscopy is expected to improve the diagnostic yield for NIN. There are two treatment strategies for NIN, observation and diagnostic therapy by endoscopic resection(ER). ER is acceptable because of its less invasiveness and high local control rate, on the other hand, cancer-developing rate of low-grade NIN is reported to be low. Therefore there is controversy for the treatment of gastric NIN. Prospective study based on unified pathological definition is required in the future.

Treatment strategy for gastric non-invasive intraepithelial neoplasia diagnosed by endoscopic biopsy

Treatment strategies,whether as follow-up or"total incisional biopsy"for gastric noninvasive intraepithelial neoplasia diagnosed by examination of an endoscopic forceps biopsy specimen,are controversial due to problems associated with the diagnostic accuracy of endoscopic forceps biopsy and questions about the safety and efficacy of endoscopic treatment.Based on the histological findings of the biopsy specimen,it is difficult to differentiate between reactive or regenerative changes,inflammation and neoplastic changes,intraepithelial and invasive tumors.Therefore,gastric neoplasia diagnosed as noninvasive intraepithelial often develop into invasive carcinoma during follow-up.Recent advances in endoscopic modalities and treatment devices,such as image-enhanced endoscopy and highfrequency generators,may make endoscopic treatment,such as endoscopic submucosal dissection(ESD),a therapeutic option for gastric intraepithelial neoplasia,including low-grade neoplasms.Future studies are required to evaluate whether ESD is a valid strategy for gastric intraepithelial neoplasm with regard to safety and cost effectiveness.

Clinical efficacy and prognostic risk factors of endoscopic radiofrequency ablation for gastric low-grade intraepithelial neoplasia

BACKGROUND The use of radiofrequency ablation(RFA)has been reported in the treatment of gastric low-grade intraepithelial neoplasia(LGIN).However,its efficacy and prognostic risk factors have not been well analyzed.AIM To explore the efficacy and prognostic risk factors of RFA for gastric LGIN in a large,long-term follow-up clinical study.METHODS The clinical data of 271 consecutive cases from 198 patients who received RFA for treatment of gastric LGIN at the Chinese PLA General Hospital from October 2014 to October 2020 were reviewed in this retrospective study.Data on operative parameters,complications,and follow-up outcomes including curative rates were recorded and analyzed.RESULTS The curative rates of endoscopic RFA for gastric LGIN at 3 mo,6 mo,and 1-5 years after the operation were 93.3%,92.8%,91.5%,90.3%,88.5%,85.7%,and 83.3%,respectively.Multivariate analyses revealed that Helicobacter pylori(H.pylori)infection and disease duration>1 year had a significant effect on the curative rate(P<0.001 and P=0.013,respectively).None of patients had bleeding,perforation,infection,or other serious complications after RFA,and the main discomfort was postoperative abdominal pain.CONCLUSION RFA was safe and effective for gastric LGIN during long-term follow-up.H.pylori infection and disease course>1 year may be the main risk factors for relapse of LGIN after RFA.

Correlation between Helicobacter pylori-associated gastric diseases and colorectal neoplasia

AIM: To explore the correlation between Helicobacter pylori(H. pylori)-associated gastric diseases and colorectal neoplasia.METHODS: Patients included in this study underwent a colonoscopy and esophago-gastro-duodenoscopy(EGD) along with histopathological measurement between March 2012 and March 2015 at Qi-Lu Hospital of Shandong University, who also had results of H. pylori detection. A total of 233 cases were selected. Demographic data, H. pylori infection status(including results of rapid urease tests and gastric mucosa pathological examinations) and histopathological examination results of gastric and colorectal mucosa were gathered and analyzed. The statistical analysis focused on the prevalence of colorectal neoplasms among patients with various histopathological categories of the stomach. ORs and their 95%CI were calculated to describe the strengths of the associations.RESULTS: The incidence rates of colorectal adenoma without high-grade intraepithelial neoplasia(HGIEN)(OR = 2.400, 95%CI: 0.969-5.941), adenoma with HGIEN(5.333, 1.025-27.758) and adenocarcinoma(1.455, 0.382-5.543) were all higher for patients with H. pylori-associated gastritis than for those in the control group. The incidence rate of colorectal adenoma with HGIEN(3.218, 0.767-13.509) was higher in patients with intestinal metaplasia than in the control group, while the incidence rates of adenoma without HGIEN(0.874, 0.414-1.845) and adenocarcinoma(0.376, 0.096-1.470) were lower in the intestinal metaplasia group than in the control group. The incidence rate of colorectal adenoma without HGIEN(3.111, 1.248-7.753) was significantly higher in the gastric intraepithelial neoplasia group than in the control group, while the rates of adenoma with HGIEN(1.481, 0.138-15.941) and adenocarcinoma(2.020, 0.561-7.272) were higher in the gastric intraepithelial neoplasia group. Incidence rates of colorectal adenoma without HGIEN(1.067, 0.264-4.314), adenoma with HGIEN(2.667, 0.231-30.800) and adenocarcinoma(2.182, 0.450-10.585) were all higher in the gastric adenocarcinoma group than in the control group.CONCLUSION: H. pylori infection as well as H. pylori-associated gastric diseases are risk factors for colorectal neoplasia.

Missed diagnosis of early gastric cancer or high-grade intraepithelial neoplasia

AIM: To investigate the causes of missed diagnosis of early gastric cancer (EGC) or high-grade intraepithelial neoplasia (HGIN) in Chongqing, China. METHODS: The present study summarizes 103 cases of EGC/HGIN detected by esophagogastroduodenos-copy (EGD) and pathological analysis from January 2010 to December 2011. Dimethyl silicone oil was administrated orally 15 min before the EGD procedures. The stomach was cleaned by repeated washing with saline when the gastroscope entered the stomach cavity. Suspected EGC lesions were subject to conventional biopsy sampling and pathological examinations. The correlation between lesion locations, endoscopic morphology of cancerous sites, training level of the examiners, pathological biopsies, and missed diagnosis was analyzed. RESULTS: Twenty-three cases were missed among the 103 cases (22.23%) of EGC/HGIN. The rate of missed EGC in the gastroesophageal junction (8/19, 42.1%) was significantly higher than at other sites (15/84, 17.86%) (χ2 = 5.253, P = 0.022). In contrast, the rate of missed EGC in the lower stomach body (2/14, 14.29%) was lower than at other sites (21/89,23.6%), but there were no significant differences (χ2 = 0.289, P = 0.591). The rate of missed EGC in the gastric antrum (5/33, 15.15%) was lower than at other sites (18/70, 25.71%), but there were no significant differences (χ2 = 1.443, P = 0.230). Endoscopists from less prestigious hospitals were more prone to not diagnosing EGC than those from more prestigious hospitals (χ2 = 4.261, P = 0.039). When the number of biopsies was < 4, the rate of missed diagnosis was higher (20/23, 89.96%) than for when there were > 4 biopsies (3/23, 13.04%) (P < 0.001). In addition, there was no significant difference in the rate of missed diagnosis in patients with 1-3 biopsy specimens (χ2 = 0.141, P = 0.932). CONCLUSION: Endoscopists should have a clear understanding of the anatomical characteristics of the esophagus/stomach, and endoscopic identification of early lesions increases with the number of biopsies.

Grasper type scissors for endoscopic submucosal dissection of gastric epithelial neoplasia

AIM:To evaluate the efficacy and safety of grasper type scissors(GTS)for endoscopic submucosal dissection(ESD)of gastric epithelial neoplasia.METHODS:The study was performed by 4 endoscopists in 4 institutions affiliated to The Catholic University of Korea.ESD was performed in 76 consecutive patients with gastric epithelial neoplasia by using the GTS(37 patients)or the hook knife plus coagrasper(HKC)(39 patients).The complete resection rate,complication rate,total time elapsed and elapsed time per square centimeter of the dissected specimen were analyzed between the GTS and HKC group.RESULTS:The mean age of the GTS group was 62.3±11.4 years and mean age of the HKC group was 65.6±10.1 years.Differentiated adenocarcinoma was found in32.4%in the GTS group and 33.3%in the HKC group.The procedures were performed without interruption in every case in both groups.The en bloc resection rates of both groups were 100%.The total time elapsed during the procedure was 44.54±21.72 min in the GTS group and 43.77±21.84 min in the HKC group(P=0.88)and the time elapsed per square centimeter of the resected lesion was 7.53±6.35 min/cm2in the GTS group and 6.92±5.93 min/cm2in the HKC group(P=0.66).The overall complication rate was not significantly different between the two groups.CONCLUSION:GTS is a safe and effective device for ESD compared with HKC.ESD can be performed with GTS alone,which can reduce the costs for ESD.

Diazepam during endoscopic submucosal dissection of gastric epithelial neoplasias

AIM:To investigate risk factors and adverse events related to high-dose diazepam administration during endoscopic submucosal dissection for gastric neoplasias.METHODS:Between February 2002 and December 2009,a total of 286 patients with gastric epithelial neoplasia underwent endoscopic submucosal dissection in our hospital.To achieve moderate sedation,5-7.5 mg of diazepam was administered intravenously by non-anesthesiologists.Intermittent additional administration of 2.5-5 mg diazepam was performed if uncontrollable body movement of the patient was observed.All patients were classified into groups based on the required diazepam dose:low-dose (≤ 17.5 mg,n=252) and high-dose (> 17.5 mg,n=79).RESULTS:Differences between the low-and highdose diazepam groups were observed in lifetime alcohol consumption (0.30 ± 0.48 vs 0.44 ± 0.52 tons,P=0.032),body weight (58.4 ± 10.3 vs 62.0 ± 9.9 kg,P=0.006),tumor size (15 ± 10 vs 23 ± 18 mm,P < 0.001),lesion location (P < 0.001) and the presence of ulcerative findings (14/238 vs 18/61,P < 0.001).Multivariate analysis identified all five variables as independently related to required diazepam dosage.In terms of adverse reactions to diazepam administration,paradoxical excitement was significantly more frequent in the high-dose diazepam group (P < 0.001).CONCLUSION:Intermittent administration of diazepam enabled safe completion of gastric endoscopic submucosal dissection except in patients who were alcohol abusers or obese,or who showed complicated lesions.

INDUCTION OF GASTRIC INTRAEPITHELIAL NEOPLASIA OF GLANDULAR STOMACH OF MONGOLIAN GERBILS BY ELICOBACTER PYLORI

Objective： To setup an animal model of gastric carcinogenesis by Helicobacter pylori （Hp） for basic, prevention and therapeutic research of Hp-related diseases. Methods： 22 young male Mongolian gerbils were administrated with suspension of Hp strain TN2 by intragastric garage for 5 consecutive times （4×10^8 CFU/time, 1 time/4 days）. 10 male gerbils were used as negative control. Two infected gerbils were killed at 10, 20, and 30 weeks, respectively, after inoculation to monitor the development of gastric lesions. Other animals were killed at 40 experimental weeks. Pathological changes of glandular stomach were examined histologically. Results： Gastric intraepithelial neoplasias （GIN） and low-grade dysplasias were observed only in the pyloric antrum of Hp-treated gerbils （3 and 2 ones, respectively）, but not in control group （5/13 vs. 0/10, P〈0.04）. High incidence of chronic active gastritis and chronic atrophic gastritis were observed in Hp-treated animals （10/13, 76.9%）. Low incidence of chronic atrophic gastritis was also detected in negative control gerbils （3/10, 30%; P〈0.04）. Conclusion： Hp inoculation could induce chronic inflammation and malignant lesions of the glandular stomach of Mongolian gerbils conveniently.

Differential gene expression profiling of gastric intraepithelial neoplasia and early-stage adenocarcinoma

AIM:To investigate the differentiated whole genome expression profiling of gastric high-and low-grade intraepithelial neoplasia and early-stage adenocarcinoma.METHODS:Gastric specimens from an upper magnifying chromoendoscopic targeted biopsy were collected from March 2010 to May 2013.Whole genome expression profiling was performed on 19 low-grade intraepithelial neoplasia(LGIN),20 high-grade intraepithelial neoplasia(HGIN),19 early-stage adenocarcinoma(EGC),and 19 chronic gastritis tissue samples using Agilent 4×44K Whole Human Genome microarrays.Differentially expressed genes between different types of lesions were identified using an unpaired t-test and corrected with the Benjamini and Hochberg false discovery rate algorithm.A gene ontology(GO)enrichment analysis was performed using the Gene Spring software GX 12.6.The differentially expressed gene was verified using a real-time TaqManPCR assay with independent tissue samples,including 26 LGIN,15 HGIN,14 EGC,and 20 chronic gastritis.The expression of G0S2 were further validated by immunohistochemical staining(IHC)in 24 LGIN,40 HGIN,30 EGC and 61 chronic gastritis specimens.RESULTS:The gene expression patterns of LGIN and HGIN tissues were distinct.There were 2521 significantly differentially expressed transcripts in HGIN,with951 upregulated and 1570 downregulated.A GO enrichment analysis demonstrated that the most striking overexpressed transcripts in HGIN compared with LGIN were in the category of metabolism,defense response,and nuclear factorκB(NF-κB)cascade.While the vast majority of transcripts had barely altered expression in HGIN and EGC tissues,only 38 transcripts were upregulated in EGC.A GO enrichment analysis revealed that the alterations of the immune response were most prominent in the progression from HGIN to EGC.It is worth noting that,compared with LGIN,289 transcriptswere expressed at higher levels both in HGIN and EGC.A characteristic gene,G0/G1 switch 2(G0S2)was one of the 289 transcripts and related to metabolism,the immune response,and the NF-κB cascade,and its expression was validated in independent samples through real-time TaqManPCR and immunohistochemical staining.In real-time PCR analysis,the expression of G0S2 was elevated both in HGIN and EGC compared with that in LGIN(P<0.01 and P<0.001,respectively).In IHC analysis,G0S2 immunoreactivity was detected in the cytoplasmic of neoplastic cells,but was undetectable in chronic gastritis cells.The G0S2 expression in HGIN was higher than that of LGIN(P=0.012,χ2=6.28)and EGC(P=0.008,χ2=6.94).CONCLUSION:A clear biological distinction between gastric high-and low-grade intraepithelial neoplasia was identified,and provides molecular evidence for clinical application.

基于GEO基因芯片联合网络药理学及分子对接技术探讨参苓脾喜汤治疗慢性胃炎、胃黏膜上皮内瘤变、胃早期癌作用机制

目的 基于GEO基因芯片、网络药理学及分子对接技术探讨参苓脾喜汤防治慢性胃炎(CG)、胃黏膜上皮内瘤变(GIN)、胃早期癌(EGC)的作用机制。方法 从GEO数据库下载含CG、GIN、EGC基因芯片GSE130823,使用R4.1.1筛选共同差异表达基因。利用TCMSP数据库筛选参苓脾喜汤活性成分及对应靶点,使用R4.1.1对共同表达基因与药物靶点取交集,通过Cytoscape3.9.1软件构建中药-活性成分-靶点网络,并通过STRING数据库构建蛋白相互作用(PPI)网络并进行拓扑分析,以筛选核心靶点,使用R4.1.1对交集基因进行GO功能和KEGG通路富集分析。最后将排名靠前的药物活性成分与核心靶点蛋白进行分子对接验证。结果 共筛选出1 115个差异表达基因,参苓脾喜汤活性成分119种,靶点247个,主要活性成分包括槲皮素、豆甾醇、木犀草素等。预测得到参苓脾喜汤治疗CG、GIN、EGC潜在作用靶点22个,包括CHRM3、AR、ADRB2、DPP4等。GO功能和KEGG富集分析结果显示,参苓脾喜汤治疗CG、GIN、EGC主要涉及对cAMP、IL-17、TNF、离子跨膜转运蛋白活性的调节、钙信号通路等方面。分子对接结果显示,木犀草素与ALB、AR、DPP4有较强结合能力,槲皮素与ALB、DPP4有较强结合能力,豆甾醇与AR有较强结合能力。结论 参苓脾喜汤中多种活性成分可能通过cAMP、IL-17、TNF等信号通路,调控ALB、AR、DPP4、CYP3A4等靶点治疗CG、GIN、EGC。

组蛋白H3K27me3沉默子重塑上调胃黏膜高级别上皮内瘤变磷酸甘油醛激酶1表达

目的 绘制胃黏膜高级别上皮内瘤变(High-Grade Intraepithelial Neoplasia, HGIN)组织的组蛋白H3K27me3沉默子图谱,寻找沉默子调控的重要靶基因。方法 从本院内镜中心收集HGIN与正常胃黏膜组织各24例,采用H3K27me3染色体靶向切割和标签化(Cleavage Under Target&Tagmentation, CUT&Tag)测序技术捕获基因组修饰区域。通过生物信息学分析比较两类组织的沉默子信号特征以及差异;整合RNA测序数据及高通量染色体构象捕获技术(Hi-C)公共数据,分析沉默子重塑调控的靶基因及调控的潜在生物学过程。结果 与正常胃黏膜相比,HGIN组织H3K27me3修饰数量减少,信号强度全局性降低,呈现H3K27me3信号峰重塑现象;转录组差异分析结果显示,与正常胃黏膜组织相比,HGIN共有8 887个差异表达基因,其中表达上调基因4 335个,表达下调基因4 552个,其中CTNNB1等肿瘤发生相关基因显著上调;整合分析表观组学和转录组学数据,发现沉默子丢失可能在转录水平上调氨基酸生物合成、精氨酸与脯氨酸代谢和糖酵解等关键代谢基因,如糖酵解关键酶磷酸甘油醛激酶1(phosphoglycerate kinase1,PGK1)表达,进而促进胃黏膜上皮内瘤变。结论 组蛋白H3K27me3沉默子信号丢失是HGIN表观重塑特征之一,沉默子丢失可能与PGK1等糖酵解和氨基酸代谢基因表达紊乱相关。

不伴幽门螺旋杆菌感染的胃黏膜低级别上皮内瘤变降级因素分析

目的:分析胃黏膜低级别上皮内瘤变(LGIN)患者的临床资料,探究不伴幽门螺旋杆菌感染(H.pylori)的LGIN降级的相关因素。方法:经纳排标准收集2012年1月至2022年12月于石河子大学第一附属医院内镜中心复诊、内镜活检并经病理回报为LGIN患者95例与病理降级患者289例的临床和病理资料。采用秩和检验、卡方检验分析基线资料,通过多因素二元Logistic回归分析筛选独立影响因素,构建预测方程并采用受试者工作特征曲线(ROC)与Hosmer-Lemeshow检验验证。结果:纳入研究的384例患者中男、女比例为1.29∶1;单因素分析显示:维持LGIN组与降级组在性别、发红、粗糙、巴黎分型IIa、IIc与IIa+IIc均存在统计学差异(均P<0.05)。多因素回归分析显示:黏膜表面粗糙是LGIN降级的保护因素(OR=0.479,95%CI 0.268~0.857),巴黎分型IIa型是LGIN降级的危险因素(OR=2.799,95%CI 1.685~4.650)。根据多因素结果构建预测LGIN病理降级方程P=ex/(1+ex),e为自然对数的底,x=0.530-0.736×黏膜表面粗糙+1.029×巴黎分型IIa型;绘制的ROC曲线下面积为0.638(95%CI 0.570~0.705);Hosmer-Lemeshow拟合度检验结果显示有较好的拟合度(χ^(2)=0.069,P=0.966)。结论:对于不伴H.pylori感染的LGIN患者存在黏膜表面粗糙与巴黎分型为非IIa型病变时,LGIN复诊诊断为病理降级的可能性小。

胃黄色瘤合并肠上皮化生的临床分析

目的 回顾性分析胃黄色瘤(gastric xanthoma,GX)合并肠上皮化生患者的临床特征。方法 选取2012年1月至2022年1月在首都医科大学宣武医院消化内镜中心初次行胃镜检查的患者共68 391例,诊断GX 1 346例,GX检出率为1.97%,平均年龄为(55.4±12.1)岁。根据有无肠上皮化生(以下简称肠化)将GX分为2组:GX伴肠化组(n=901)和GX不伴肠化组(n=445)。对比两组患者的年龄、性别、幽门螺杆菌(Helicobacter pylori,HP)感染、胃黏膜萎缩程度及是否合并胃癌情况。将GX伴肠化组再根据肠化的程度分为3个亚组:GX伴轻度肠化(n=412)、GX伴中度肠化(n=291)和GX伴重度肠化(n=198),对比分析不同亚组GX伴肠化的临床特征。结果 GX伴肠化与GX不伴肠化组在年龄(P=0.012)、HP感染(P<0.001)和是否合并胃癌(P=0.014)方面差异有统计学意义;GX伴肠化组中年龄≥65岁患者发病率较高、HP感染率高、合并胃癌的检出率较高。单因素及多因素分析显示GX患者中胃癌组和非胃癌组在年龄(P<0.001)、HP感染(P<0.001)、胃黏膜萎缩程度(P<0.001)及GX是否伴有肠化(P=0.014)等方面比较差异有统计学意义。3个亚组在年龄(P<0.001)、性别(P=0.004)、胃黏膜萎缩程度(P<0.001)和胃癌(P<0.001)上均差异均有统计学意义。GX伴中度、重度肠化组中,老年人比例较高(P=0.002,P=0.008),GX伴轻度肠化组中各种程度胃黏膜萎缩均为最轻(P<0.001),GX伴重度肠化组合并重度胃黏膜萎缩程度最高(P<0.001)且合并胃癌比例较高(P<0.001)。结论 GX伴肠化的发生与胃癌、萎缩性胃炎及其严重程度有关,需要多中心、大样本对照研究进一步论证。