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Recently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated.We evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS).Among 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%).Overall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations.

Objectives: We aimed to clarify the endoscopic and clinicopathological features of raspberry-shaped gastric lesions (RSGLs) and to establish an endoscopic diagnostic algorithm for RSGLs. Methods: We collected RSGLs from an endoscopic database at our hospital between May 2009 and August 2021. All RSGLs were histopathologically classified and compared based on their endoscopic and clinicopathological characteristics. Results: Sixty-five RSGLs in 54 patients were classified into five histopathological types: gastric adenocarcinoma of foveolar type (GA-FV, n = 43), gastric adenocarcinoma of fundic-gland type (GA-FG, n = 2), gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM, n = 4), hyperplastic polyp (HP, n = 12), and proton pump inhibitor-related lesion (PPI-L, n = 4). All RSGLs exhibited polygonal or curved marginal crypt epithelium (MCE). GA-FV lesions had homogenously reddish (95%) and irregular microvascular (MV) pattern (91%). GA-FG lesions were heterogeneously reddish with a submucosal tumor shape (100%) and had a regular MV pattern (50%). GA-FGM lesions were homogenously reddish (75%) and occasionally had a submucosal tumor shape (50%) with an irregular MV pattern (75%). HP and PPI-L were homogeneously reddish (93%), with linear or dotted MCE (81%) and a regular MV pattern (100%). Conclusion: Our diagnostic algorithm for RSGLs constructed using endoscopic features might be useful for the endoscopic differential diagnosis of RSGLs.

A mediastinal thoracic duct cyst that originates from the thoracic duct is a very rare disease in the mediastinum. There have been no reports of mediastinal thoracic duct cyst infection caused by endoscopic treatment. This is the first case of mediastinal thoracic duct cyst infection after endoscopic submucosal dissection for early esophageal cancer. We herein report a 75-year-old man with mediastinal thoracic duct cyst infection caused by esophageal endoscopic submucosal dissection. In cases where a mediastinal thoracic duct cyst is found before performing endoscopic esophageal treatment, we should carefully consider the potential risk of post-treatment cyst infection.

Evaluation of chronic constipation is important, although it is often difficult to satisfactorily treat due to the complex interplay of factors. This study aimed to determine whether the volume of intraluminal contents and lateral diameter of the colon measured from computed tomography (CT) images were correlated with the symptoms of chronic constipation and stool consistency. Consecutive patients who underwent the Constipation Scoring System (CSS), Bristol Stool Form Scale (BSFS) questionnaires and simple abdominal CT were selected retrospectively. The intestinal tract diameter at each site was measured, and the amounts of stool and gas in the intestinal tract were evaluated at five levels. Of the 149 study participants, 54 were males and 95 were females and their mean age was 72.1 years. In the right hemi-colon, CSS5 (Time) correlated significantly with gas volume (p < 0.01). In the left hemi-colon, stool volume correlated significantly with CSS2 (Difficulty), CSS3 (Completeness), CSS5 (Time) and CSS total (p < 0.05). The BSFS negatively correlated with gas volume and diameter in the right hemi-colon and with gas volume in the rectum (p < 0.05). CT findings including stool volume, gas volume and diameter correlated with some constipation symptoms and stool consistency. These findings may be useful in evaluating and treating constipation.

We herein report a rare case of Yersinia enterocolitica enteritis with a fever and abdominal pain followed by erythema nodosum (EN) a few days later. The diagnosis was confirmed based on characteristic colonoscopy and computed tomography findings, pathology, and mucosal culture. Yersinia enteritis is a curable disease provided a proper diagnosis and treatment are performed. Although EN is a rare clinical course, it should still be considered as a differential diagnosis.

The incidence of gastric cancer in Okinawa Prefecture is the lowest in Japan, which is attributed to differences in strains of

Bile acids are strongly associated with the pathogenesis of functional gastrointestinal diseases. In recent years, blue laser imaging (BLI) endoscopy has emerged as a novel image-enhanced endoscopic method, which illustrates bile as a reddish hue. The present study investigated the factors that affect the area of bile in duodenal bulbs using BLI. For this purpose, patients (356 cases) who underwent upper endoscopy with BLI between April, 2017 and December, 2019, and completed patient background and symptom questionnaires [Constipation Scoring System (CSS), Bristol Stool Form Scale (BSFS) and Frequency Scale for Symptoms of gastroesophageal reflux disease (FSSG)], were retrospectively investigated. Each BLI bile score was calculated as a percentage of bile area in a field of view in the duodenal bulb using a KS400 image analysis system, and the association with abdominal symptoms was examined using multiple regression analysis. The patient characteristics included the following: Age (in years), 69.9±11.3; male/female ratio, 146/210; body mass index, 23.0±3.8; reflux esophagitis (M/A/B/C), 143/19/3/3; atrophic gastritis (C-0/C1-3/O1-3), 132/100/124; proton pump inhibitor potassium competitive acid blocker/aspirin/ursodeoxycholic acid/gall bladder stones/cholecystectomy, 105/27/18/43/18; BLI bile score, 7.10 (±14.34); CSS score, 3.55 (±3.80); BSFS score, 3.91 (±1.02); and FSSG score, 4.80 (±5.76). Correlation coefficients (P0.05) for the BLI bile score were found for cholecystectomy (Rho=0.137) and aspirin use (Rho=0.118). In multiple regression analysis, independent predictors of the BLI bile score were cholecystectomy [standardized partial regression coefficient (β)=0.169, P=0.001] and the BSFS score (β=0.107, P=0.042). On the whole, the present study demonstrates that the duodenal bile area in BLI upper endoscopy is associated with cholecystectomy and fecal characteristics.

Video Video 1 A case of improved visibility with gel immersion in the presence of ongoing bleeding during colorectal endoscopic submucosal dissection.

Background and Aim Magnifying endoscopy (ME) diagnostic algorithm for early gastric cancer (EGC) relies on qualitative features such as microvascular (MV) architecture and microsurface structure; however, it is a “static” diagnostic algorithm that uses still images. ME can visualize red blood cell flow within subepithelial microvessels in real time. Here, we evaluated the utility of using the MV blood flow rate in combination with ME for the diagnosis of EGC as a retrospective study. Methods Patients with differentiated‐type EGC (n = 10) or patchy redness (n = 10) underwent ME with blue laser imaging. The mean MV blood flow rates of EGC, patchy redness, and background mucosa were calculated by the mean movement distance of one tagging red blood cell using split images of ME with blue laser imaging videos. We compared the mean MV blood flow rate between EGC, patchy redness, and background mucosa and also calculated the MV blood flow imaging ratio (inside lesion/background mucosa) between EGC and patchy redness. Results Mean MV blood flow rate was significantly lower in EGC (1481 μm/s; range 1057–1762) than in patchy redness (3859 μm/s; 2435–5899) or background mucosa (4140.6 μm/s; 2820–6247) (P

Background: Gastric adenocarcinoma of foveolar type (GA-FV) is a raspberry-shaped gastric cancer (RSGC) and garners much attention as H. pylori (Hp)-uninfected gastric cancer. However, the classification and clinicopathological and endoscopic features of RSGCs in Hp-uninfected patients are poorly defined. We designed a new histopathological classification of RSGC and compared them via endoscopic and clinicopathological characteristics. Summary: From 996 patients with early gastric cancers resected by endoscopy in our hospital, we studied 24 RSGC lesions from 21 (2.4%) Hp-uninfected patients. RSGCs were classified into 3 histological types as follows: GA-FV (n = 19), gastric adenocarcinoma of fundic gland type (GA-FG, n = 2), and gastric adenocarcinoma of fundic gland mucosa type (GA-FGM, n = 3). Most of the lesions were found at the greater curvature of the upper or middle third of the stomach. GA-FV lesions were homogeneously reddish and frequently accompanied with a whitish area around the tumor and an irregular microvascular (MV) pattern; these features were confirmed histopathologically by the presence of homogeneous neoplastic foveolar epithelium with foveolar hyperplasia around the tumors. GA-FG lesions might be heterogeneously reddish with a submucosal tumor shape and regular MV pattern; these were confirmed by the presence of covered or mixed nonneoplastic epithelium on deeper regions of tumors. GA-FGM lesions might be homogeneously reddish and occasionally had a submucosal tumor shape and irregular MV pattern; these were confirmed by the presence of homogeneous neoplastic foveolar epithelium on deeper regions of the tumors. Key Messages: RSGCs in Hp-uninfected patients are classified into 3 histopathological types. For accurate diagnosis of RSGCs, it may be necessary to fully understand endoscopic features of these lesions based on these histological characteristics and to take a precise biopsy.

Background With more prevalent gastroesophageal reflux disease comes increased cases of Barrett's esophagus and esophageal adenocarcinoma. Image-enhanced endoscopy using linked-color imaging (LCI) differentiates between mucosal colors. We compared LCI, white light imaging (WLI), and blue LASER imaging (BLI) in diagnosing reflux esophagitis (RE). Methods Consecutive RE patients (modified Los Angeles [LA] classification system) who underwent esophagogastroduodenoscopy using WLI, LCI, and BLI between April 2017 and March 2019 were selected retrospectively. Ten endoscopists compared WLI with LCI or BLI using 142 images from 142 patients. Visibility changes were scored by endoscopists as follows: 5, improved; 4, somewhat improved; 3, equivalent; 2, somewhat decreased; and 1, decreased. For total scores, 40 points was considered improved visibility, 21–39 points was comparable to white light, and E*) and L* a* b* color values in RE and adjacent esophageal mucosae were assessed using CIELAB, a color space system. Results The mean age of patients was 67.1 years (range: 27–89; 63 males, 79 females). RE LA grades observed included 52 M, 52 A, 24 B, 11 C, and 3 D. Compared with WLI, all RE cases showed improved visibility: 28.2% (40/142), LA grade M: 19.2% (10/52), LA grade A: 34.6% (18/52), LA grade B: 37.5% (9/24), LA grade C: 27.3% (3/11), and LA grade D: 0% (0/3) in LCI, and for all RE cases: 0% in BLI. LCI was not associated with decreased visibility. The LCI inter-rater reliability was “moderate” for LA grade M and “substantial” for erosive RE. The LCI intra-rater reliability was “moderate–substantial” for trainees and experts. Color differences were WLI: 12.3, LCI: 22.7 in LA grade M; and WLI: 18.2, LCI: 31.9 in erosive RE (P Conclusion LCI versus WLI and BLI led to improved visibility for RE after subjective and objective evaluations. Visibility and the ICC for minimal change esophagitis were lower than for erosive RE for LCI. With LCI, RE images contrasting better with the surrounding esophageal mucosa were more clearly viewed.

Background and study aims Magnifying endoscopy with narrow band imaging (M-NBI) has made a huge contribution to endoscopic diagnosis of early gastric cancer (EGC). However, we sometimes encountered false-negative cases with M-NBI diagnosis (i. e., M-NBI diagnostic limitation lesion: M-NBI-DLL). However, clinicopathological features of M-NBI-DLLs have not been well elucidated. We aimed to clarify the clinicopathological features and histological reasons of M-NBI-DLLs. Patients and methods In this single-center retrospective study, M-NBI-DLLs were extracted from 456 EGCs resected endoscopically at our hospital. We defined histological types of M-NBI-DLLs and analyzed clinicopathologically to clarify histological reasons of M-NBI-DLLs. Results Of 456 EGCs, 48 lesions (10.5 %) of M-NBI-DLLs were enrolled. M-NBI-DLLs was classified into four histological types as follows: gastric adenocarcinoma of fundic-gland type (GA-FG, n = 25), gastric adenocarcinoma of fundic-gland mucosal type (GA-FGM, n = 1), differentiated adenocarcinoma (n = 14), and undifferentiated adenocarcinoma (n = 8). Thirty-nine lesions of M-NBI-DLLs were H. pylori-negative gastric cancers (39/47, 82.9 %). Histological reasons for M-NBI-DLLs were as follows: 1) completely covered with non-neoplastic mucosa (25/25 GA-FG, 8/8 undifferentiated adenocarcinoma); 2) well-differentiated adenocarcinoma with low-grade atypia (1/1 GA-FGM, 14/14 differentiated adenocarcinoma); 3) similarity of surface structure (10/14 differentiated adenocarcinoma); and 4) partially covered and/or mixed with a non-neoplastic mucosa (1/1 GA-FGM, 6/14 differentiated adenocarcinoma). Conclusions Diagnostic limitations of M-NBI depend on four distinct histological characteristics. For accurate diagnosis of M-NBI-DLLs, it may be necessary to fully understand endoscopic features of these lesions using white light imaging and M-NBI based on these histological characteristics and to take a precise biopsy.

Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.

Objective The association between frailty and abdominal symptoms has not been evaluated. Methods We conducted a hospital-based, retrospective cross-sectional study of consecutive outpatients ≥65 years old at the Department of Gastroenterology, Juntendo Tokyo Koto Geriatric Medical Center from 2017 to 2019. Patients were included in the study if all of the following information was available from their medical records: patient's profile, the evaluation of osteoporosis, sarcopenia, frailty, nutritional status, findings of upper gastrointestinal endoscopy, and questionnaire results for abdominal symptoms [Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Constipation Scoring System (CSS)]. We divided the subjects into frailty and non-frailty groups and investigated the risk factors for frailty. Results Of the 313 eligible study subjects [134 men (42.8%) and 179 women (57.2%); mean age, 75.7±6.0 years; mean body mass index, 22.8±3.6 kg/m2], frailty was noted in 71 cases (22.7%). In a univariate analysis, an older age (p

Background and Aim Magnifying 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. Methods The 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. Results The 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. Conclusions The 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.

Cancer metastasis, particularly multiple metastatic cancer, is a significant event that affects patient prognosis. However, single metastasis can be treated by partial resection, although the clinicopathological and molecular profile of single lung metastasis has not been thoroughly elucidated. The present study examined tumor heterogeneity by comparing the mutation status between primary colorectal cancer (CRC) and corresponding metastatic lesions to identify prognostic factors associated with single lung metastasis and multiple metastases. The present study enrolled 31 cases of CRC; 20 cases with multiple metastases and 11 cases with single lung metastasis. Clinicopathologically, all cases with multiple metastases were tubular adenocarcinoma, and 3/11 cases with single metastasis were mucinous adenocarcinoma originating from the left side, the remaining 8 cases were tubular adenocarcinoma from the left side. CRC cases with multiple metastases exhibited more frequent vascular invasion, but not lymphatic invasion, than those with single lung metastasis. Furthermore, CRC with multiple metastases was associated with strong tumor budding (P=0.04). Patients with CRC with multiple metastases had lower recurrence-free survival rates compared with those with single lung metastasis (P=0.02). However, there was no significant difference between these two groups in terms of overall survival rates. A next-generation sequencing cancer hotspot panel was used to analyze a heterochronous multiple metastases case, including brain metastasis. Sanger sequencing, immunohistochemistry and microsatellite instability were examined for all 31 cases to reveal the molecular features. KRAS and TP53 mutation signatures were largely preserved throughout the metastatic events. TP53/APC mutations and overexpression of p53 appeared to be associated with the presence of lymphovascular invasion and strong tumor budding, respectively, although these differences were not statistically significant. Early relapses in patients with CRC could be a sign for eventual multiple metastases, although these may not affect the overall survival of patients with CRC. Considerable mutational changes were seemingly rare during metastatic events in patients with CRC.

The incidence of gastric cancer in Okinawa Prefecture is the lowest in Japan, which is attributed to differences in strains of Helicobacter pylori in Okinawa and other prefectures in Japan. Our aim was to compare the endoscopic findings of H. pylori-infected gastric mucosa in Okinawa and Tokyo. Patients who underwent upper gastrointestinal endoscopy (UGI) at Northern Okinawa Medical Center (Okinawa group) and Juntendo University Hospital (Tokyo group) from April 2019 to March 2020 were included. Patients diagnosed with H. pylori-infected gastric mucosa were retrospectively compared between the Okinawa and Tokyo groups according to the Kyoto Classification of Gastritis. The numbers of subjects (Okinawa/Tokyo) were 435/352, male/female ratio was 247:188/181:171, and age was 53.3 ± 14.7/64.6 ± 14.3 (mean ± standard deviation) years. Regarding the Kyoto Classification of Gastritis, the prevalence (Okinawa/Tokyo) of the closed type of atrophic gastritis was 73%/37% (p < 0.001), diffuse redness 80%/84% (p = 0.145), mucosal swelling 46%/46% (p = 0.991), enlarged fold 26%/32% (p = 0.048), spotty redness 77%/68% (p = 0.002), sticky mucus 17%/36% (p < 0.001), and intestinal metaplasia 32%/42% (p < 0.001). Age analysis also revealed that closed-type atrophy and spotty redness were more frequent in the Okinawa group than in the Tokyo group. There may be regional differences in endoscopic findings of H. pylori-infected gastric mucosa between Okinawa and Tokyo.

Introduction: Whether the incidence of reflux esophagitis (RE) increases after the eradication of Helicobacter pylori (H. pylori) is controversial. Few reports have evaluated the presence or absence of RE after a long period of time, taking into account the degree of atrophy and/or administration of acid secretion inhibitors. We investigated the relationship between H. pylori and RE taking into account these factors. Methods: This was a retrospective cohort study with approval by the Ethics Committee. Patients who succeeded in H. pylori eradication treatment, and in whom there were images of the gastroesophageal junction on endoscopic examinations within 1 year before eradication treatment and more than 3 years after eradication were included. The degrees of RE and atrophy were retrospectively determined from the endoscopic images. The prevalence of RE before and after eradication and the incidence of newly developed RE after eradication between patients with or without atrophy improvement were compared using Fisher’s exact test. Results: A total of 185 cases (male:female = 104:81; mean age, 63.5 years; mean observation period, 6.4 years) were examined. The prevalence of RE before and after eradication was 1.6% (3/185) and 7.0% (13/185), respectively (P = 0.019). RE was present in 8 (7.5%) of 106 cases with closed-type atrophy and in 5 (6.3%) of 79 cases with open-type atrophy after eradication (P = 0.75). Atrophy improved after eradication in 56 cases, of whom 4 (7.1%) had new onset of RE; the degree of atrophy did not improve in 126 cases, of whom 7 (5.4%) had new onset of RE (P = 0.74). There was no difference between the percentage of cases who took acid secretion inhibitors before and after eradication (P = 0.14). Conclusion: The prevalence of RE increased a long time after eradication, even in patients who were taking an acid secretion inhibitor. The prevalence of RE was not related to the degree of atrophy or change in atrophy.

Background and study aims We developed an e-learning program for endoscopic diagnosis of invasion depth of early gastric cancer (EGC) using a simple diagnostic criterion called non-extension sign, and the contribution of self-study quizzes to improvement of diagnostic accuracy was evaluated. Methods We conducted a prospective randomized controlled study that recruited endoscopists throughout Japan. After completing a pretest, the participants watched video lectures and undertook post-test 1. The participants were then randomly allocated to either the self-study or non-self-study group, and participants in the first group completed the self-study program that comprised 100-case quizzes. Finally, participants in both groups undertook post-test 2. The primary endpoint was the difference in post-test 2 scores between the groups. The perfect score for the tests was set as 100 points. Results A total of 423 endoscopists completed the pretest and were enrolled. Post-test 1 was completed by 415 endoscopists and 208 were allocated to the self-study group and 207 to the non-self-study group. Two hundred and four in the self-study group and 205 in the non-self-study group were included in the analysis. Video lectures improved the mean score of post-test 1 from 72 to 77 points. Participants who completed the self-study quizzes showed significantly better post-test 2 scores compared with the non-self-study group (80 vs. 76 points, respectively, P Conclusions Our e-learning program showed that self-study quizzes consolidated knowledge of the non-extension sign and improved diagnostic ability of endoscopists for invasion depth of EGC.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.

Distinguishing undifferentiated-type from differentiated-type early gastric cancers (EGC) is crucial for determining the indication of endoscopic resection. We aimed to investigate the diagnostic performance of white-light endoscopy (WLE) and magnifying narrow-band imaging (M-NBI) for the histological type of EGC.In this multicenter prospective study, patients with histologically proven cT1 EGC, macroscopically depressed or flat type, size ≥5 mm, and without erosion/ulcer, were recruited. The diagnostic criterion of WLE for undifferentiated-type EGC was pale color. The M-NBI algorithm was created based on microsurface and microvascular patterns, and lesions with absent microsurface pattern and opened-loop microvascular patterns were diagnosed as undifferentiated-type. The center of the lesion was defined as the evaluation point and was initially evaluated by WLE, then by M-NBI, and a biopsy specimen was taken as a reference standard. The primary and key secondary endpoints were overall diagnostic accuracy and specificity, respectively.In total, 167 lesions (122 differentiated-type and 45 undifferentiated-type EGCs) in 167 patients were analyzed. The overall accuracy, sensitivity, specificity, and positive likelihood ratio of WLE for undifferentiated-type cancer were 80%, 69%, 84%, and 4.4, respectively, and those of M-NBI were 82%, 53%, 93%, and 7.2, respectively. There was no significant difference in overall accuracy (The use of M-NBI did not improve the accuracy of WLE for the diagnosis of depressed/flat undifferentiated-type EGCs but improved the specificity. It may reduce surgical overtreatment by preventing misdiagnosis of differentiated-type EGC as undifferentiated-type.

Background Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. Methods One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. Results GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. Conclusions We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.