Multicenter study of invasive gastric cancer detected after 10 years of Helicobacter pylori eradication in Japan: Clinical, endoscopic, and histopathologic characteristics.

Objectives: Gastric cancer can be diagnosed even in patients long after Helicobacter pylori eradication. Most cases involve intramucosal lesions; however, some are invasive and require surgery. To clarify appropriate long-term surveillance methods, this study compared invasive gastric cancer diagnosed ≥10 and <10 years after eradication. Methods: This retrospective multicenter study included 14 institutions. We included 377 patients with gastric cancer with submucosal or deep invasion after surgical or endoscopic resection. Ordered logistic regression analysis was used to explore the factors contributing to the pathological stage and histological type. Results: Invasive gastric cancer was detected in 84 patients (Group L) and 293 patients (Group S) ≥10 and <10 years after H. pylori eradication, respectively. Endoscopic mucosal atrophy at the time of cancer detection was similar in both groups; 50% of the patients had severe atrophy. Annual endoscopy correlated with early pathological stage (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.14-0.54, p < 0.001). Group L exhibited an independent correlation with the advanced pathological stage (OR 2.27, 95% CI 1.06-4.88, p = 0.035) and the undifferentiated type (OR 2.12, 95% CI 1.16-3.90, p = 0.015). The pure differentiated type and early pathological stage significantly (p = 0.001) correlated with severe mucosal atrophy in Group S but not in Group L. Conclusions: Invasive cancers diagnosed ≥10 years after H. pylori eradication were likely to be more malignant in histological type and pathological stage. Gastric cancer surveillance should continue regardless of endoscopic atrophy, particularly ≥10 years after eradication.

Metastatic pancreatic cancer with multiple metastases confined to the large intestine: a case report and literature review.

The incidence and mortality rate of pancreatic cancer are increasing worldwide. Regional lymph nodes, liver, lung, and peritoneum are common sites of metastasis from pancreatic cancer, but the gastrointestinal tract is rare as a metastatic organ from pancreatic cancer. An 80-year-old man was referred to our department for a hypovascular pancreatic mass on contrast-enhanced computed tomography (CECT). Endoscopic ultrasound-guided fine needle aspiration revealed adenocarcinoma, and he was diagnosed with pancreatic cancer. No lymph nodes or distant metastases were detected by either CECT or gadolinium-enhanced magnetic resonance imaging, and we evaluated this case as borderline resectable. However, total colonoscopy for positive fecal occult blood tests revealed a reddish and hemorrhagic mucosal thickening in the ascending and sigmoid colon and rectum, which was inconsistent with primary colorectal cancer. Biopsy specimens from these sites revealed cytokeratin (CK)7-positive and CK20- and CDX2-negative adenocarcinoma, consistent with cancer of pancreatic origin. The patient underwent palliative chemotherapy with gemcitabine but died from COVID-19 infection eight months after diagnosis. Performing total colonoscopy as a preoperative screening is important for accurate cancer staging of patients with possible resectable pancreatic cancer.

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.

Colonic amyloidosis: Rare endoscopic findings mimicking a depressed neoplastic lesion.

A colonic depressed lesion was found in a 77-year-old man and suspected as a neoplastic lesion using conventional endoscopy. Magnifying endoscopy, however, did not support it and biopsy revealed the lesion to be AL amyloidosis.

Analysis of prognostic factors in patients with self-expandable metallic stents for treatment of malignant gastric outlet obstruction.

BACKGROUND AND AIM: Self-expandable metallic stents (SEMSs) are widely accepted as a less-invasive treatment for malignant gastric outlet obstruction (GOO). However, the factors related to prognosis and stent dysfunction after SEMS placement are not well known, and we aimed to investigate them. METHODS: This was a single-center retrospective cohort study of 212 malignant strictures in 207 patients. Factors related to prolonged overall survival (OS) and time to recurrent GOO (TRGOO) after SEMS placement were evaluated. RESULTS: Improvement of oral intake was confirmed in 179 patients (86%). The median OS was 65 days. A Cox proportional hazards model revealed that lower cancer stage, lower performance status score at the time of SEMS placement, and administration of chemotherapy after SEMS placement were significant predictive factors for prolonged OS. The median OS was 182 days in the group of SEMS followed by chemotherapy (group A) and 43 days in the group of SEMS alone (group B) (p< .0001). Chemotherapy after SEMS implantation contributed to the prolongation of survival in gastric cancer (hazard ratio (HR), 0.12) and pancreatic cancer (HR, 0.41). Furthermore, the cumulative incidence rates of stent dysfunction on day 120 after SEMS placement were 30% in group A and 61% in group B (p=.03). Notably, the preventive effect of chemotherapy on stent dysfunction was significant in pancreatic cancer. CONCLUSIONS: SEMS is a treatment with high technical and clinical success rate for malignant GOO. Furthermore, subsequent chemotherapy prolongs OS especially in gastric cancer, and TRGOO in pancreatic cancer.

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma.

Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization.

Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization. SIGNIFICANCE: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.

Gastric Hyperplastic Polyps Can Shrink After Discontinuation of Proton Pump Inhibitors: A Case Series Compared With Continuation of Proton Pump Inhibitors.

GOAL: This study investigated whether gastric hyperplastic polyps (GHPs) shrink after discontinuation of proton pump inhibitor (PPI) alone. BACKGROUND: Long-term use of PPIs has been reported to increase the incidence of GHPs, which sometimes bleed and cause anemia. We experienced a patient whose recurrent hemorrhagic GHPs associated with long-term use of PPIs had disappeared after discontinuation of PPIs. STUDY: This study was conducted retrospectively at Kyoto University Hospital. Patients with histologically confirmed GHPs who had been taking PPIs for >6 months and who had undergone a repeat endoscopy within 2 years were included. Polyp shrinkage was defined as the disappearance of polyps or a reduction of >50% in the long diameter of the largest polyp. RESULTS: Six patients who discontinued PPIs were compared with 17 patients who continued PPIs. Polyp shrinkage was significantly more frequent in the PPI-discontinuation group (5/6, 83%) than in the PPI continuation group (0/17, 0%) (P<0.001). In 2 patients in the PPI-discontinuation group, the polyps completely disappeared finally. CONCLUSION: These findings suggest that discontinuation of PPIs can shrink GHPs in patients using PPIs.

Long-term improvement in constipation-related symptoms after Helicobacter pylori eradication therapy.

BACKGROUND: Helicobacter pylori eradication therapy effectively improves the abnormal bowel habits and abdominal symptoms of patients for a few months post-treatment (PT). However, it is unclear whether the improvement in abnormal bowel habits and symptoms continues long term. Here, we investigated the association of successful H. pylori eradication therapy with improvements in abdominal symptoms in the short- and long-term PT. MATERIALS AND METHODS: We evaluated the severity of constipation-related abdominal symptoms in 287 H. pylori-positive patients who underwent eradication therapy at pre-treatment and 2 and 12 months PT using two measures: the Gastrointestinal Symptom Rating Scale (GSRS) and the Izumo scale. RESULTS: In patients with constipation at pre-treatment, constipation-related symptom scores in the GSRS improved significantly from 7.91 ± 3.15 at pre-treatment to 6.07 ± 2.75 at 2 months PT (p < 0.01) and 6.85 ± 3.46 at 12 months PT (p = 0.04). Patients with improved symptom scores at 2 months PT also experienced an improvement at 12 months PT. In contrast, patients who did not experience an improvement in constipation-related symptoms at 2 months PT likewise did not experience an improvement at 12 months PT. CONCLUSIONS: Patients who experience an improvement at 2 months PT with H. pylori eradication therapy continue to experience improved symptoms in the long term. Therefore, H. pylori -positive patients with abnormal bowel habits should be recommended eradication therapy to prevent gastric cancer development and to alleviate abnormal bowel habits and abdominal symptoms.

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Immunoglobulin A vasculitis without purpura in an elderly female patient: a case report.

Immunoglobulin A (IgA) vasculitis mainly affects the joints, skin, kidneys, and gastrointestinal tract; however, purpura is an essential diagnostic criterion. Here, we report an unusual case of IgA vasculitis without purpura in an elderly woman. A 76-year-old woman was admitted to our hospital complaining of diarrhea and abdominal pain. No skin rash, purpura, jaundice, or peripheral lymphadenopathy was observed. Endoscopy of the small intestine revealed severe mucosal sloughing in the duodenum, and a biopsy specimen showed severe erosive duodenitis. A decrease in coagulation factor XIII (FXIII) activity was also observed during laboratory blood tests. IgA immunostaining revealed granular IgA deposition on the walls of the interstitial small blood vessels. Although the patient showed no purpura or renal involvement, a diagnosis of IgA vasculitis was made based on the histopathology findings from biopsies. The administration of purified FXIII concentrate improved her symptoms immediately and facilitated regeneration of the duodenal villi. When gastroenterologists encounter severe erosive duodenitis or inflammation of the small intestine, IgA vasculitis should be listed as part of the differential diagnosis even without purpura and/or renal involvement. For a definitive diagnosis, measurement of FXIII and IgA immunostaining using duodenal biopsy specimens should be performed actively.

Spontaneous regression of mismatch repair-deficient colorectal cancers: Case series.

Spontaneous regression (SR) has been reported in various malignant tumors. However, SR in colorectal cancer (CRC) is particularly rare and the mechanism remains unclear. We here report three cases of CRCs displaying SR, which were experienced at two institutions. Intriguingly, all of these cases displayed the common endoscopic characteristics; superficial elevated lesion accompanied by a central depression (0-IIa + IIc, in the Paris classification), with a nonpolypoid growth, located in the ascending colon. Furthermore, immunohistology of biopsy specimens revealed the lack of DNA mismatch repair proteins within the CRC lesions, suggesting that these were mismatch repair-deficient (dMMR) CRCs. One of the major features of dMMR cancers is an increase in the number of tumor-infiltrating lymphocytes. Thus, the dMMR phenotype might be associated with SR of CRCs through the activation of anti-tumor host immune responses.

Endoscopic laryngopharyngeal surgery for hypopharyngeal lesions.

OBJECTIVES: Transoral approaches for laryngeal/pharyngeal malignancies have been widely accepted as minimally invasive treatment options; however, hypopharyngeal lesions treated by transoral surgery have rarely been reported due to the difficulties in visualizing the hypopharynx. Since 2010, we have treated superficial hypopharyngeal lesions with endoscopic laryngopharyngeal surgery (ELPS), and herein report the outcomes of this transoral procedure. MATERIALS AND METHODS: One hundred and eighteen patients with superficial hypopharyngeal lesions were treated by ELPS from February 2010 to February 2017, and the clinical courses of the patients were reviewed. RESULTS: Four females and 114 males (average: 65.6 y-o) were included in this study. Some patients had multiple lesions and a total of 154 superficial hypopharyngeal lesions (dysplasia: 29, Tis: 52, T1: 44, T2: 20, T3: 9) were treated with ELPS. Ten patients had only dysplasia and no carcinoma. Five patients presented with nodal metastases and 11 patients had simultaneous oropharyngeal lesions. In all cases, the hypopharynx was well visualized with sufficient working space, and no cases required a change in surgical approach. All post-operative complications were safely managed. In regard to the oncological outcomes, of the 108 patients with malignant lesions, the 3-year and 5-year overall survival (OS) rate was 93.6% and 85.5%, respectively. CONCLUSIONS: During ELPS, the hypopharynx was well visualized providing sufficient working space for the resection. The procedure was safe and feasible for superficial hypopharyngeal lesions and exhibited very good oncological outcomes. ELPS is thought to be a very effective surgical alternative for superficial hypopharyngeal lesions.

Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice.

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.