Multiple intraductal papillary neoplasms of bile duct diagnosed based on endoscopic ultrasonography and peroral cholangioscopy findings.

A man in his 30s was referred to our department for evaluation of bile duct stricture and removal of an intrahepatic bile duct stone. Five years before his presentation, he underwent left hepatectomy for a giant hepatic hemangioma. There were no abnormalities in blood biochemical tests. Magnetic resonance cholangiopancreatography showed one 5 mm oval defect in region B6 and two 8 mm semicircular defects in the hilar bile duct. Endoscopic ultrasound revealed a 3.5 mm hypoechoic focal raised lesion in the hilar bile duct. Oral cholangioscopy revealed his two lesions in the hilar bile duct as white papillary elevations with mucus production. The pathological diagnosis of intraductal papillary neoplasm was determined (low-grade dysplasia, type 1, gastric type). After 1 and a half years, no expansion of the bile duct lesion was observed. Initially, it was thought to be a benign stenosis after liver resection, but based on the results of endoscopic ultrasound, we suspected a tumorous lesion, and we were able to make an accurate diagnosis, including histological type, using transoral cholangioscopy.

Gastric dysplastic lesions in Helicobacter pylori-naïve stomach: Foveolar-type adenoma and intestinal-type dysplasia.

Reports of Helicobacter pylori (Hp)-naïve gastric neoplasm (HpNGN) cases have been rapidly increasing due to the recent increase in the Hp-naïve population in Japan. Most HpNGNs exhibit the gastric immunophenotype and a low malignant potential regardless of histological type. Especially, foveolar-type gastric adenoma (FGA) and intestinal-type gastric dysplasia (IGD) rarely progress to invasive carcinoma. FGA is a foveolar epithelial neoplasm that occurs in the fundic gland (oxyntic gland) mucosa and is classified as the flat type or raspberry type (FGA-RA). The flat type is a large, whitish flatly elevated lesion while FGA-RA is a small reddish polyp. Genomically, the flat type is characterized by APC and KRAS gene mutations and FGA-RA by a common single nucleotide variant in the KLF4 gene. This KLF4 single-nucleotide variant reportedly induces gastric foveolar epithelial tumorigenesis and activates both cell proliferation and apoptosis, leading to its slow-growing nature. IGD consists of an intestinalized epithelial dysplasia that develops in the pyloric gland mucosa, characterized as a superficial depressed lesion surrounded by raised mucosa showing a gastritis-like appearance. Immunohistochemically, it exhibits an intestinal or gastrointestinal phenotype and, frequently, p53 overexpression. Thus, IGD shows unique characteristics in HpNGNs and a potential multistep tumorigenic process.

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.

Gastric Metastasis from Salivary Duct Carcinoma Mimicking Scirrhous Gastric Cancer.

A 59-year-old man underwent submandibular gland excision for salivary duct carcinoma (SDC). One year later, esophagogastroduodenoscopy indicated gastric diffuse mucosal thickening with luminal contraction, mimicking scirrhous gastric carcinoma. Biopsy specimens showed dense proliferation of neoplastic cells expressing androgen receptor and human epidermal growth factor 2, indicating SDC. Gastric diffuse infiltrative metastasis is generally characteristic of gastric metastasis from invasive ductal carcinoma, which shows histologic features similar to SDC. This is the first known report of gastric diffusely infiltrating metastasis in an SDC patient. Rapidly progressing, diffuse gastric wall thickening should also be considered indicative of salivary tumor-associated gastric metastasis.

Clinicopathologic differences of gastric neoplasms between Helicobacter pylori-infected and -naïve patients: a multicenter retrospective analysis.

BACKGROUND: The incidence of gastric neoplasms in Helicobacter pylori (Hp)-naïve patients has recently increased due to a remarkable decrease in the Hp-infected population in Japan. We investigated the clinicopathologic differences between Hp-infected gastric neoplasms (HpIGNs) and Hp-naïve gastric neoplasms (HpNGNs) that have not been fully elucidated so far. METHODS: This retrospective multicenter study investigated 966 consecutive patients with 1131 gastric dysplasia or cancers who underwent endoscopic or surgical treatment for the recent decade. Clinicopathologic features were compared between HpIGN and HpNGN cases. RESULTS: One thousand and sixty-eight HpIGNs in 916 patients included 877 differentiated types and 191 undifferentiated types. Sixty-three HpNGNs in 50 patients included 57 differentiated types (35 foveolar types, 15 intestinal types, 6 fundic-gland types, and 1 other differentiated type) and 6 undifferentiated types. HpNGNs occurred in younger (59.5 vs. 71.8 years, p < 0.05) and female patients (40.0% vs. 26.5%, p < 0.05), were found more frequently in the proximal compartment (p < 0.05), and had smaller size (median 4.0 vs. 20.0 mm, p < 0.05). Histologically, HpNGNs and HpIGNs both primarily consisted of differentiated type (90.5% vs. 82.1%, p = 0.089) and HpNGNs showed lower prevalence of invasive cancer (11.1% vs. 37.6%, p < 0.05) and lymphovascular invasion (1.6% vs. 31.6%, p < 0.05). Nearly all HpNGNs (62/63, 98.4%) were diagnosed in early pathological stage, while 16.1% (172/1068) of HpIGNs were diagnosed in advanced stage (p < 0.05). CONCLUSIONS: HpNGNs is recently on the increase but shows lower malignant nature regardless of histologic type than HpIGN. Endoscopic gastric cancer screening will be reviewed via cost effectiveness for Hp-naïve individuals in future.

Endoscopic differential diagnosis between foveolar-type gastric adenoma and gastric hyperplastic polyps in Helicobacter pylori-naïve patients.

BACKGROUND: Foveolar-type gastric adenoma (FGA) occurs in Helicobacter pylori (Hp)-naïve individuals and morphologically mimics Hp-naïve gastric hyperplastic polyp (HpN-GHP). FGA is often difficult to distinguish from HpN-GHP even by biopsy, due to its low-grade histologic atypia. We conducted a retrospective study to create an endoscopic diagnostic index. METHODS: We analyzed 51 FGAs in 41 patients and 36 HpN-GHPs in 24 patients. All lesions were photographed by white-light endoscopy (WLE) and narrow-band imaging with magnification endoscopy (NBIME). Three experts and three non-experts reviewed the WLE and WLE+NBIME images to assess six items for lesion diagnosis. We analyzed correlations between the diagnostic items and histologic features and compared the diagnostic accuracy between modalities. We created a composite diagnostic index and calculated its accuracy and consistency. RESULTS: FGAs more frequently showed the following features vs. HpN-GHPs: bright-red color (94.1% vs. 44.4%), peripheral hyperplasia (58.8% vs. 8.3%), papillary/gyrus-like microstructure (96.1% vs. 33.3%), visible capillaries (70.6% vs. 38.9%), and demarcation line (98.0% vs. 41.7%) (P < 0.05). White-zone thickening was seen only in HpN-GHPs (52.8%). Diagnostic accuracy (mean, WLE vs. WLE+NBIME) was 90.8 ± 1.1% vs. 93.5 ± 2.4% (P = 0.15) for experts and 88.5 ± 3.0% vs. 86.6 ± 3.5% (P = 0.51) for non-experts. When satisfying the four criteria (bright-red color, papillary/gyrus-like microstructure, demarcation line, and absent white-zone thickening), sensitivity and specificity for FGA were 90.2% and 94.4%, respectively, with a kappa value of ≥ 0.6 for interobserver diagnostic agreement. CONCLUSIONS: Composite diagnostic index contributes to the reproducible, accurate, preoperative differential diagnosis of FGA and HpN-GHP.

KLF4 Mutation Shapes Pathologic Characteristics of Foveolar-Type Gastric Adenoma in Helicobacter pylori-Naive Patients.

Along with a recent remarkable decrease in Helicobacter pylori-infected individuals, reports of gastric neoplasms such as sporadic foveolar-type gastric adenoma (FGA) in H. pylori-naive patients have been increasing. This tumor, with its raspberry-like appearance, is common in H. pylori-naive gastric mucosa. The current study investigated the genomic features of sporadic FGA. Fresh-frozen sporadic FGA tissue samples from H. pylori-naive patients were subjected to whole genome analysis using a next-generation sequencer. Proliferation ability and apoptotic profiles of human gastric epithelial cells, along with plasmid transfection of candidate variants, were examined. A mean of 6.65 × 108 total reads were obtained for each sample. Common genetic abnormalities in well-known proliferation driver genes of conventional gastric dysplasia/cancer were not found. However, a common single-nucleotide variation (SNV) was noted within the DNA-binding domain of the tumor suppressor gene KLF4. This novel SNV was located in the zinc finger 2 region. Additional experiments showed that it significantly suppressed proliferation of gastric epithelial cells compared with wild-type KLF4 plasmid-transfected cells, although suppression was reduced in early apoptotic phase-related genes. A novel SNV in the KLF4 zinc finger 2 region was commonly found in sporadic FGA tissue samples, which may explain the slow-growing properties of this neoplasm.

Long-lasting renal dysfunction following tacrolimus induction therapy in ulcerative colitis patients.

Although tacrolimus (TAC) has remarkable effects in ulcerative colitis (UC) patients when given as remission induction therapy, some can develop renal dysfunction during TAC administration, resulting in withdrawal, though related details remain poorly understood. This study was conducted to determine the impact of oral TAC on renal function for remission induction therapy in UC patients. Fifty-five patients (10 elderly, 45 non-elderly) with UC and treated with oral TAC at our hospital were retrospectively evaluated. Renal function was assessed using estimated glomerular filtration rate (eGFR). Although a high clinical response to TAC was seen in both elderly and non-elderly, a decline in eGFR was noted in nearly all patients regardless of age, with a maximum change of -34.4% from the baseline value at week 11. Furthermore, eGFR decline recovered quickly after TAC discontinuation, though did not return to the baseline at two years following cessation. The rate of eGFR change at week 12 was significantly associated with patient age (ß = -0.3242, p = 0.0103) and peak serum trough level during TAC treatment (ß = 0.3563, p = 0.0051). Furthermore, the rate of decline in eGFR was significantly greater during treatment with TAC in the elderly as compared to non-elderly, with a large difference in eGFR decline rate between those groups also noted at two years after withdrawal of treatment. Careful attention to renal function when administering oral TAC for UC is important and changes in eGFR should be monitored closely in elderly patients even after treatment cessation.

Effectiveness of second-look endoscopy after gastric endoscopic submucosal dissection in patients taking antithrombotic agents: a multicenter propensity score matching analysis.

BACKGROUND: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents. METHODS: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis. RESULTS: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140). CONCLUSIONS: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

Risk factors and prediction of bleeding after gastric endoscopic submucosal dissection in patients on antithrombotic therapy: newly developed bleeding prediction application software, SAMURAI model.

Bleeding after gastric endoscopic submucosal dissection (ESD) remains problematic, especially in patients receiving antithrombotic therapy. Therefore, this study aimed to identify the risk factors. In this retrospective study, patients (n = 1,207) who underwent gastric ESD while receiving antithrombotic therapy were enrolled at Osaka Medical and Pharmaceutical University Hospital and 18 other referral hospitals in Japan. Risks of post-ESD bleeding were calculated using multivariable logistic regression. The dataset was divided into a derivation cohort and a validation cohort. We created a prediction model using the derivation cohort. The accuracy of the model was evaluated using the validation cohort. Post-ESD bleeding occurred in 142 (11.8%) participants. Multivariable analysis yielded an odds ratio of 2.33 for aspirin, 4.90 for P2Y12 receptor antagonist, 1.79 for cilostazol, 0.95 for other antithrombotic agents, 6.53 for warfarin, 5.65 for dabigatran, 7.84 for apixaban, 10.45 for edoxaban, 6.02 for rivaroxaban, and 1.46 for heparin bridging. The created prediction model was called safe ESD management using the risk analysis of post-bleeding in patients with antithrombotic therapy (SAMURAI). This model had good predictability, with a C-statistic of 0.77. In conclusion, use of the SAMURAI model will allow proactive management of post-ESD bleeding risk in patients receiving antithrombotic therapy.

Oxaliplatin-related Portal Hypertension Complicated with Esophageal Varices and Refractory Massive Ascites.

Oxaliplatin, widely used as a chemotherapy drug for colorectal cancer, is known to cause various adverse reactions. In particular, special attention for the development of portal hypertension associated with porto-sinusoidal vascular disease is necessary, as it is a serious adverse life-threating reaction, although rare. We herein report a case of oxaliplatin-related portal hypertension that developed several years after oxaliplatin administration and led to esophageal varices and refractory massive ascites. Clinical physicians should be aware of the possibility of oxaliplatin-induced portal hypertension and its possible development over a long period after discontinuation of the drug.

Heterotopic Gastric Mucosa in Middle Esophagus Complicated with Esophageal Ulcers.

Heterotopic gastric mucosa (HGM) of esophagus, primarily occurring in cervical esophagus, is usually asymptomatic. A healthy woman (mid-40s) with postprandial heartburn was diagnosed with middle esophageal HGM and esophageal ulcers by esophagogastroduodenoscopy. Using 8-channel pH monitoring, a sensor near the HGM area detected postprandial acid phase (pH 3-4), while areas adjacent to the proximal and distal sensors were neutral, suggesting acid secretion from the HGM. A biopsy showed fundic gland tissue expressing H+/K+-ATPase and pepsinogen-I. Oral vonoprazan improved the clinical symptoms and endoscopic findings. This is the first report using 8-channel pH monitoring to diagnose extremely rare middle esophageal HGM.

Endoscopic diagnosis and screening of Barrett's esophagus: Inconsistency of diagnostic criteria between Japan and Western countries.

Barrett's esophagus (BE) is an endoscopically identifiable premalignant condition for esophageal adenocarcinoma (EAC). To diagnose BE precisely, careful inspection of the anatomic landmarks, including the esophagogastric junction and the squamocolumnar junction is important. The distal end of the palisade vessels and the proximal end of the gastric folds are used as the landmark of the esophagogastric junction in endoscopic diagnosis, with the latter solely used internationally, except in some Asian countries, including Japan. In addition, the diagnostic criteria adopted internationally for BE are inconsistent, particularly between Japan and Western countries. Recently updated guidelines in Western countries have included length criteria, with a 1-cm threshold of columnar epithelium by endoscopic observation and/or histologic confirmation of the presence of specialized intestinal metaplasia. Since BE is endoscopically diagnosed at any length without histologic assessment in Japan, the reported prevalence of short-segment BE is very high in Japan compared with that in Western countries. Although guidelines on screening exist for BE, the current strategies based on the presence of chronic gastroesophageal reflux disease with multiple risk factors may miss the opportunity for early detection of EAC. Indeed, up to 40% of patients with EAC have no history of chronic gastroesophageal reflux disease. To discuss BE on the same footing worldwide, standardization of diagnostic criteria, screening indication, and establishment of effective techniques for detecting dysplastic lesions are eagerly awaited. Japanese guidelines for BE should be revised regarding the length criteria, including the minimum length and long-segment BE, in line with the recently updated Western guidelines.

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.

Intestinal-type gastric dysplasia in Helicobacter pylori-naïve patients.

Gastric dysplasia and gastric cancer in Helicobacter pylori (Hp)-naïve patients usually exhibit a gastric phenotype, reflecting gastric mucosa without intestinal metaplasia (IM). We showed that intestinal-type gastric dysplasia (IGD) rarely occurs in the Hp-naïve stomach. In the last 10 years, we treated 1760 gastric dysplasia and gastric cancer patients, with 3.6% (63/1760) being Hp-naïve. Among these, ten were diagnosed with 14 IGDs and enrolled in this retrospective analysis. All lesions were observed by white-light endoscopy (WLE) and narrow-band imaging with magnification endoscopy (NBIME). We analyzed their endoscopic and microscopic features and patient demographics. Five men and five women aged 64 ± 21 years were included. WLE showed the depressed lesions mimicking a benign raised erosion in the prepyloric compartment. Multiple growths were confirmed in 30% (3/10) of patients. NBIME showed a near-regular microstructure and capillaries in 50% (7/14) of lesions with a gastritis-like appearance. Histologically, background mucosa was non-atrophic pyloric gland tissue, but 40.0% of samples (4/10) contained sporadic IM. Most of the lesions (8/14) were low-grade dysplasia, and others had a high-grade component, with one progressing to intramucosal carcinoma. The neoplastic surface was widely covered with foveolar epithelium in 57.1% (8/14). Immunohistochemically, neoplastic cells expressed CDX2 in all patients (14/14), MUC2 and CD10 in 92.9% (13/14), MUC5AC in 14% (2/14), and no expression of MUC6, showing an intestinal phenotype. Ki-67 was overexpressed with a mean labeling index of 58.3 ± 38.5%, and p-53 was overexpressed in 92.9% (13/14), regardless of the dysplastic grade. The IGD rarely occurs in Hp-naïve patients with distinctive clinicopathologic characteristics.

A multicenter prospective study of the treatment and outcome of patients with gastroduodenal peptic ulcer bleeding in Japan.

Gastroduodenal peptic ulcers are the main cause of nonvariceal upper gastrointestinal bleeding (UGIB). We believe that recent advances in endoscopic techniques and devices for diagnosing upper gastrointestinal tract tumors have advanced hemostasis for UGIB. However, few prospective multicenter studies have examined how these changes affect the prognosis. This prospective study included 246 patients with gastroduodenal peptic ulcers treated at 14 participating facilities. The primary endpoint was in-hospital mortality within 4 weeks, and the secondary endpoints required intervention and refractory bleeding. Subsequently, risk factors affecting these outcomes were examined using various clinical items. Furthermore, the usefulness of the risk stratification using the Glasgow-Blatchford score, rockall score and AIMS65 based on data from the day of the first urgent endoscopy were examined in 205 cases in which all items were complete there are two periods. Thirteen (5%) patients died within 4 weeks; and only 2 died from bleeding. Significant risk factors for poor outcomes were older age and severe comorbidities. Hemostasis was required in 177 (72%) cases, with 20 cases of refractory bleeding (2 due to unsuccessful endoscopic treatment and 18 due to rebleeding). Soft coagulation was the first choice for endoscopic hemostasis in 57% of the cases and was selected in more than 70% of the cases where combined use was required. Rockall score and AIMS65 predicted mortality equally, and Glasgow-Blatchford score was the most useful in predicting the requirement for intervention. All scores predicted refractory bleeding similarly. Although endoscopic hemostasis for UGIB due to peptic ulcer had a favorable outcome, old age and severe comorbidities were risk factors for poor prognosis. We recommend that patients with UGIB should undergo early risk stratification using a risk scoring system.

Primary Extragastrointestinal Stromal Tumor of Greater Omentum with Intraperitoneal Bleeding.

Gastrointestinal stromal tumors (GISTs) develop in the digestive tract, mainly in the stomach, small intestine, colon, or esophagus. However, primary tumors with the same pathologic features as GISTs have been reported to occur outside of the digestive tract and are called extragastrointestinal stromal tumor (EGIST). We herein report a rare case of EGIST arising from the greater omentum in a patient with abdominal pain caused by intraperitoneal bleeding from the tumor.