Endoscopic features of synchronous multiple early gastric cancers: Findings from a nationwide cohort.

INTRODUCTION: We investigated the factors associated with synchronous multiple early gastric cancers and determined their localization. METHODS: We analyzed 8191 patients who underwent endoscopic submucosal dissection for early gastric cancers at 33 hospitals in Japan from November 2013 to October 2016. Background factors were compared between single-lesion (n=7221) and synchronous multi-lesion cases (n=970) using univariate and multivariate analyses. We extracted cases with two synchronous lesions (n=832) and evaluated their localization. RESULTS: Significant independent risk factors for synchronous multiple early gastric cancer were older age (≥75 years old) (OR=1.257), male sex (OR=1.385), severe mucosal atrophy (OR=1.400), tumor localization in the middle (OR=1.362) or lower region (OR=1.404), and submucosal invasion (OR=1.528 (SM1), 1.488 (SM2)). Depressed macroscopic type (OR=0.679) and pure undifferentiated histology OR=0.334) were more common in single early gastric cancers. When one lesion was in the upper region, the other was more frequently located in the lesser curvature of the middle region. When one lesion was in the middle region, the other was more frequently located in the middle region or the lesser curvature of the lower region. When one lesion was in the lower region, the other was more frequently located in the lesser curvature of the middle region or the lower region. CONCLUSION: Factors associated with synchronous multiple early gastric cancer included older age, male sex, severe mucosal atrophy, tumor localization in the middle or lower region, and tumor submucosal invasion. Our findings provide useful information regarding specific areas that should be examined carefully when one lesion is detected.

Gender Differences in Patients with Gastric Adenocarcinoma.

Background: Gastric cancer (GC) epidemiology and outcomes vary by gender. Methods: We reviewed 18,436 GC patients from 2008 to 2018 and looked for gender differences in clinical characteristics and survival. Results: The gender proportion was 71% male and 29% female. Males had a significantly (p < 0.001) higher proportion of differentiated GC (66.3%) and a lower proportion of undifferentiated GC (26.3%). Diagnosis through medical check-ups was more common in males (30.0% vs. 26.4%, p < 0.001). Clinical staging revealed 54.6% of males and 52.9% of females had localized disease without lymph node metastasis (LNM), while distant metastasis occurred in 17.4% of males and 16.9% of females (p < 0.001). Kaplan-Meier survival curves indicated females had a significantly higher overall survival (p = 0.0018). The survival advantage for females was evident in the early stages, with a significant difference in localized disease without LNM (p < 0.001) and localized disease with LNM (p = 0.0026, log-rank test) but not in the advanced stages. Multivariate Cox regression analysis showed a significantly reduced mortality risk in females (p < 0.001). Conclusions: Significant gender differences exist with regard to pathological type, presentation, clinical stage, and overall survival. These findings suggest gender-specific strategies for screening, diagnosis, and treatment.

A new grading assessment of eosinophilic esophagitis using red dichromatic imaging: A pilot study.

BACKGROUND AND AIMS: The endoscopic reference score (EREFS) using white light imaging (WLI) is used for evaluating the severity of findings objectively in patients with eosinophilic esophagitis (EoE). A novel image-enhanced endoscopy, red dichromatic imaging (RDI) can visualize deeper vessels in the gastrointestinal tract, which could assess edema more precise than WLI. METHODS: A total of 21 consecutive patients with EoE were prospectively evaluated. Patients were categorized by three grades based on the visibility of vessels with RDI. Clinical features, such as peak eosinophil counts (PEC) and presence of symptoms, were reviewed. RESULTS: There were 10 patients with RDI Grade 0/1, and 11 patients with RDI Grade 2. PEC and the prevalence of heartburn were significantly higher in patients with RDI Grade 2 than in patients with RDI Grade 0/1. CONCLUSIONS: The severity of eosinophilic infiltration could be predicted more precisely using RDI than by evaluating with WLI.

Prevalence and risk factors for medication-refractory reflux esophagitis in patients with systemic sclerosis in Japan.

BACKGROUNDS: Patients with systemic sclerosis (SSc) often have esophageal motility abnormalities and weak esophago-gastric junction (EGJ) barrier function, which causes proton pump inhibitor (PPI)-refractory reflux esophagitis (RE). The aims of this study were to clarify the current management of RE and prevalence and risk factors of medication-refractory RE in patients with SSc in Japan. METHODS: A total of 188 consecutive patients with SSc who underwent both esophageal high-resolution manometry (HRM) and esophagogastroduodenoscopy (EGD) were reviewed. The presence of RE and grades of the gastroesophageal flap valve (GEFV) were assessed. Esophageal motility was assessed retrospectively according to the Chicago classification v3.0. When RE was seen on a standard dose of PPI or any dose of vonoprazan (VPZ), it was defined as medication-refractory RE. RESULTS: Approximately 80% of patients received maintenance therapy with acid secretion inhibitors regardless of esophageal motility abnormalities. Approximately 50% of patients received maintenance therapy with PPI, and approximately 30% of patients received VPZ. Medication-refractory RE was observed in 30 patients (16.0%). In multivariable analyses, the number of EGD and absent contractility were significant risk factors for medication-refractory RE. Furthermore, combined absent contractility and GEFV grade III or IV had higher odds ratios than did absent contractility alone. CONCLUSIONS: Patients with persistent reflux symptoms and those with absent contractility and GEFV grade III or IV should receive maintenance therapy with strong acid inhibition to prevent medication-refractory RE.

Evaluating the efficacy and safety of acotiamide in patients with esophagogastric junction outflow obstruction: study protocol for an investigator-initiated, multi-center, randomized, double-blind, placebo-controlled phase II trial.

BACKGROUND: We have determined that the impaired accommodation of the lower esophageal sphincter (LES) underlies the pathogenesis of esophagogastric junction outflow obstruction (EGJOO). We have also found that acotiamide may treat EGJOO by improving impaired LES accommodation. The effects of acotiamide in patients with EGJOO need to be further confirmed in a prospective study. METHODS: This trial is a multicenter, randomized, double-blind, placebo-controlled study to compare the efficacy and safety of acotiamide (300 mg/day or 600 mg/day) with those of a placebo in the treatment of patients with EGJOO. The primary endpoint will be the proportion of patients who report an improvement in symptom of food sticking in the chest after 4 weeks of treatment period 1. The secondary endpoints will be the proportion of patients with normalized integrated relaxation pressure (IRP), the value of change from baseline in the distal contractile integral, basal LES pressure, EGJOO-quality of life score, Gastrointestinal Symptom Rating Scale, and the correlation between IRP and each symptom score. During the 2-year trial period, 42 patients from five institutions will be enrolled. DISCUSSION: This trial will provide evidence to clarify the efficacy and safety of acotiamide as a treatment for patients with EGJOO. Acotiamide might help improve the quality of life of patients with EGJOO and is expected to prevent the progression of EGJOO to achalasia. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of Kyushu University Hospital as well as the local IRBs of the participating sites for clinical trials and registered in the Japan Registry of Clinical Trials (jRCT: 2071210072). The registration date is on October 11, 2021.

Concurrent chemoradiotherapy using proton beams can reduce cardiopulmonary morbidity in esophageal cancer patients: a systematic review.

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence.

A Marked Eosinophilic Infiltration in Mucosa Could Be a Better Predictive Factor for Intractable Non-Esophageal Eosinophilic Gastrointestinal Disorders.

INTRODUCTION: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are rare, but their prevalence has recently increased. Although it has been reported that one-half of patients with non-EoE EGIDs have intractable clinical courses, their clinical features are not fully understood. METHODS: This is a multicenter retrospective study in which 10 institutions in Japan participated. Clinical databases from January 1998 to December 2020 were reviewed to identify patients with non-EoE EGIDs. A total of 44 patients were identified; they were divided into two groups based on their clinical course: an intractable group and a non-intractable group. The clinical features were compared between the two groups by a logistic regression analysis. Remarkable eosinophilic infiltration (REI) was defined histologically when the maximal counts of mucosal eosinophils reached a threshold level in the respective area of biopsy. RESULTS: Prevalence of drug allergy and eosinophil counts more than 500/µL (EOS), vomiting symptoms, abnormalities of the stomach, duodenum, and jejunum on computed tomography (upper gastrointestinal abnormality on computed tomography [UACT]), and REI were significantly different between the two groups. Among the factors that were potentially associated with an intractable clinical course, logistic regression revealed that REI, EOS, and UACT were significant factors. Based on an analysis of the area under the receiver operator characteristic curve, a combination of REI and EOS had the lowest Akaike's information criterion, indicating the best model to predict an intractable clinical course. CONCLUSIONS: REI may predict an intractable course in patients with non-EoE EGIDs. In addition, the combination of REI and EOS was a better predictor than REI alone.

The relationship between manometric subtype and symptom details in achalasia.

BACKGROUND: Although dysphagia and chest pain are the two most common symptoms in patients with achalasia, the mechanism of evoking symptoms is still unknown. The aim of this study was to reveal the relationship between symptoms and the subtypes of achalasia defined by the Chicago classification. METHODS: A total of 71consecutive patients with newly diagnosed achalasia were enrolled between March 2009 and December 2017. Esophageal motility was assessed by high-resolution manometry (HRM) with the Chicago classification v 3.0. and esophagograms. Their symptoms were evaluated with structured self-reported questionnaires focused on dysphagia and chest pain. Symptom profiles and radiographic findings according to the manometric subtypes were investigated. RESULTS: Among the total 71 patients, 69 patients (97%) had dysphagia and 39 patients (54%) had chest pain. Regarding dysphagia, type II patients reported dysphagia in the throat the most, while types I and III patients mostly felt it in the epigastrium. Type II patients often felt dysphagia at the time of swallowing (41%), but this was reported in only 8.7% of Type I and 33% of Type III patients (p = 0.02). Concerning chest pain, Type I patients rarely had pain during meals (14%), but more often while sleeping (43%) and in early morning (43%), while type III patients often had pain during meals (67%). Type III patients reported that solid food caused pain more often than other types (I/II/III 0/10/33%, p = 0.09). CONCLUSIONS: Detailed symptoms of achalasia, such as its site and timing, varied by subtypes. The status of the esophageal body might induce those differences in symptoms.

Usefulness of Endoscopy for the Detection and Diagnosis of Primary Esophageal Motility Disorders and Diseases Relating to Abnormal Esophageal Motility.

Esophagogastroduodenoscopy (EGD) is performed to rule out organic diseases in the diagnosis of esophageal motility disorders (EMDs). Abnormal endoscopic findings can be observed during EGD, which indicate the presence of EMDs. Several endoscopic findings at both the esophagogastric junction and esophageal body that are related to EMDs have been reported. Gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) could be detected during EGD, and these diseases are often associated with abnormal esophageal motility. Image-enhanced endoscopy (IEE) could improve the detection of these diseases during EGD. Although no report has been published previously on the potential usefulness of IEE in the endoscopic diagnosis of EMDs, IEE can be used to detect disorders that can be associated with abnormal esophageal motility.

Validation of red dichromatic imaging score (RDI score) to evaluate the severity of ulcerative colitis.

BACKGROUND: Red dichromatic imaging (RDI) is a new imaging technology that has been closely correlated with the activity index of ulcerative colitis (UC). Although the RDI score has been developed no study has validated a correlation between the RDI score and the activity index of UC. Therefore, this study aims to validate the RDI score prospectively. METHODS: A total of 34 patients with UC in whom colonoscopy was scheduled between May 2019 and October 2021 at our hospital were enrolled prospectively. MES, UCEIS, RDI scores, and Nancy index were evaluated in a blinded fashion. We evaluated the correlation between RDI and WLI scores using still images with histology. RESULTS: We analyzed 191 sites of colorectum. RDI score showed the positive correlation with UCEIS (r = 0.74 P < 0.0001) and MES (r = 0.78 P < 0.0001). RDI score also showed the positive correlation with Nancy index (r = 0.63 P < 0.0001). RDI score was more strongly correlated with Nancy index than UCEIS (r = 0.51) and MES (r = 0.48). CONCLUSIONS: When comparing still images of RDI and WLI scores, we showed RDI had a higher correlation to histology than WLI. CLINICAL TRIAL ID: The University Hospital Medical Information Network (UMIN000041750).

Association between perioperative management of antiplatelet agents and risk of post-endoscopic submucosal dissection bleeding in early gastric cancer: analysis of a nationwide multicenter study.

BACKGROUND AND AIMS: Data are lacking regarding post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.

Efficacy of using red dichromatic imaging throughout endoscopic submucosal dissection procedure.

BACKGROUND: Management of bleeding during endoscopic submucosal dissection (ESD) is critical. Red Dichromatic Imaging (RDI), a novel image-enhanced endoscopy technology, has been reported to improve the visibility of deep vessels and bleeding source compared to white light imaging (WLI). We hypothesized that using RDI during the entire cutting process (full time RDI ESD: FTR-ESD), higher R0 resection rate, shorter procedure time and fewer complications could be achieved. Therefore, the aims of the present study were to investigate the efficacy and safety of FTR-ESD. METHODS: This retrospective observational study included a total of 82 consecutive patients who underwent ESD by a single expert endoscopist for 40 esophageal, 17 gastric and 25 colorectal cancers at our institution from January 2018 to March 2021. The clinicopathological data were collected from patients' medical records and the treatment outcomes were analyzed according to the treatment phase (early; 57 WLI-ESD and late; 25 FTR-ESD). RESULTS: The median of the greatest diameter of resected specimen was 40.0 mm. The median procedure time was relatively shorter in the FTR-ESD group (35 min) than in the WLI-ESD group (40 min), but the difference was not statistically significant (p = 0.34). The median dissection speed in the FTR-ESD group (27.23 mm2/min) was significantly faster than that in the WLI-ESD group (20.94 mm2/min) (p = 0.025). The dissection speed was not different among different organs. A multivariate analysis revealed that tumor size (more than 30 mm) and FTR-ESD were significant independent factors contributing to faster dissection speed (p < 0.05). There were no significant differences in the rates of en bloc resection, HM0, VM0 or occurrence of adverse events between WLI-ESD and FTR-ESD. CONCLUSIONS: FTR-ESD significantly increases the dissection speed compared to WLI-ESD. FTR-ESD can be performed safely and therapeutic outcomes in FTR-ESD are comparable with WLI-ESD. A further multicenter prospective study is warranted to confirm our results.

High-resolution manometry with additional maneuvers using the Starlet system: normative thresholds and diagnostic yields for relevant esophagogastric junction outflow disorders.

BACKGROUND: Chicago classification version 4.0 suggests additional maneuvers, such as upright testing, multiple rapid swallows (MRS), and the rapid drink challenge (RDC), for high-resolution manometry (HRM) to minimize ambiguity in the diagnosis of esophageal motility disorders. The present study investigated normative thresholds for these new metrics using the Starlet system as well as their diagnostic yields for relevant esophagogastric outflow disorders (EGJOD). METHODS: In study 1, 30 asymptomatic volunteers prospectively performed HRM including MRS and RDC in the supine/upright positions. We calculated normative thresholds for the new metrics, such as upright integrated relaxation pressure (IRP), upright intrabolus pressure (IBP), and IRP during RDC (RDC-IRP). In study 2, we retrospectively analyzed the HRM tracings of 82 patients who underwent HRM in both positions at our hospital to assess the diagnostic yields of HRM metrics. RESULTS: Based on the results of study 1, we adopted the following normative thresholds: upright IRP < 20 mmHg, upright IBP < 21 mmHg, and RDC-IRP < 16 mmHg. In study 2, 45 patients with dysphagia or chest pain were included in the analysis to identify predictive factors for clinically relevant esophagogastric outflow disorders (true EGJOD). Supine/upright IRP, RDC-IRP, and pan-esophageal pressurization > 20 mmHg during RDC (RDC-PEP) predicted true EGJOD with RDC-PEP with the highest sensitivity of 91.7%. CONCLUSIONS: HRM with additional maneuvers may facilitate the diagnosis of clinically relevant EGJOD.

[Ulcerative colitis complicated by pyoderma gangrenosum and multiple aseptic abscesses].

A woman in her 30s was diagnosed with ulcerative colitis (UC) 4 years ago and treated with tacrolimus, azathioprine, and prednisolone 5mg (PSL). Skin ulcers appeared on the right lower leg during the course of treatment, diagnosed as pyoderma gangrenosum (PG). The patient initially improved with an increased PSL and infliximab dose, but then developed multiple skin ulcers and folliculitis throughout her body. She was transferred to our hospital for PG exacerbation treatment. She developed fever after transfer and contrast-enhanced computed tomography showed multiple abscesses in the lungs and kidneys. PSL was decreased and infliximab was discontinued. Antibiotic therapy and granulocyte/monocyte apheresis (GMA) were started. Fever persisted even after antibiotic treatment, and her general condition did not improve. A right renal abscess puncture was performed. Pus was sterile. A sterile abscess associated with PG was suspected. The PSL dose was increased to 1mg/kg and infliximab restarted. Thereafter, the patient's general condition improved, and both lung and renal abscesses contracted. Skin ulcer epithelialization was also observed. Abdominal symptoms were mild during the course of the disease, and colonoscopy showed only a localized ulcerative lesion in the rectum. The patient was later transferred to the department of dermatology at our hospital for PG treatment. Aseptic abscesses are caused by neutrophil infiltration without infection and have been reported to be associated with neutrophilic dermatosis and inflammatory bowel disease. UC-associated aseptic abscess is rare. This is only the sixth case in Japan. Aseptic abscesses can occur in various sites, including subcutaneous and deep organs, but this is the first kidney abscess case. In previous reports, PSL, infliximab, colchicine, and infliximab+GMA were used for aseptic abscesses associated with UC. They all showed abscess reduction. Aseptic abscesses associated with PG should be considered if abscess lesions occur during the course of UC, and a treatment strategy including enhanced immunosuppression should be considered.

Bleeding following Endoscopic Submucosal Dissection for Early Gastric Cancer in Surgically Altered Stomach.

INTRODUCTION: Few studies have focused on bleeding following endoscopic submucosal dissection (ESD) in surgically altered stomach. We aimed to reveal the bleeding risk in surgically altered stomach following ESD for early gastric cancer (EGC). METHODS: We enrolled patients with ESD for EGC at 33 institutions between 2013 and 2016. In study 1, we evaluated bleeding risk following ESD in surgically altered stomach, compared with whole stomach. In study 2, we evaluated factors associated with bleeding following ESD in patients with surgically altered stomach. RESULTS: Of 11,452 patients, 445 patients had surgically altered stomach with the bleeding rate following ESD of 4.9%. In study 1, the bleeding risk in surgically altered stomach was not significant (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.87-2.17) in the multivariate logistic regression analysis. No significant results were obtained when the surgically altered stomach was subdivided into various types. In study 2, the multivariate logistic regression analysis revealed that independent risk factors for bleeding following ESD were ischemic heart disease (OR, 7.52; 95% CI, 2.00-28.25) and P2Y12 receptor antagonist (OR, 4.81; 95% CI, 1.21-19.14). DISCUSSION/CONCLUSION: In this nationwide study, we found that the bleeding risk of surgically altered stomach following ESD for EGC did not significantly differ from that of whole stomach. The risk factors for ESD in patients with surgically altered stomach were ischemic heart disease and P2Y12 receptor antagonist.