A Case of Refractory Gastroesophageal Reflux Disease Successfully Treated with Endoscopic Anti-gastroesophageal Reflux Mucosal Resection by the ESD-G Method (with video).

A 70-year-old man who had undergone treatment for gastroesophageal reflux disease (GERD) by a family doctor presented to our hospital with severe heartburn and dysphagia despite taking vonoprazan (20 mg) for 3 months. A diagnosis of vonoprazan-refractory nonerosive reflux disease was made based on esophagogastroduodenoscopy and esophageal function examinations. The patient elected to undergo endoscopic treatment for GERD. Therefore, we performed endoscopic treatment using the endoscopic submucosal dissection (ESD-G) technique developed at our institution. After endoscopic treatment, his GERD symptoms disappeared and he no longer required GERD-related medications. An examination of his esophageal function revealed the improvement of items related to GERD.

Background factors of idiopathic peptic ulcers and optimal treatment methods: a multicenter retrospective Japanese study.

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.

Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

Frontiers in Endoscopic Treatment for Gastroesophageal Reflux Disease.

BACKGROUND: The 3rd edition of the evidence-based clinical practice guidelines for gastroesophageal reflux disease (GERD) 2021 from the Japanese Society of Gastroenterology states that the treatment strategy for potassium-competitive acid blocker (PCAB)-refractory GERD remains unclear. Furthermore, even if GERD improves with the administration of an acid secretion inhibitor, it is feared that GERD may flare up after discontinuation of the drug, resulting in some cases in which patients are forced to take vonoprazan semipermanently (the so-called PCAB-dependent cases). From a global perspective, PCAB is not yet used in all countries and regions, and measures that can be taken now for cases in which a conventional proton pump inhibitor (PPI) is inadequately effective need to be devised. SUMMARY: Endoscopic treatment for GERD may be effective in cases where conventional proton pump inhibitors are ineffective; however, there are insufficient long-term studies to corroborate this, and its cost effectiveness is unknown. Other treatment options for PCAB or PPI-refractory GERD include surgical procedures (Nissen and Toupet operations), which have a longer history than endoscopic treatment for GERD. However, their long-term results are not as good as those of acid secretion inhibitors, and they are not cost effective. Endoscopic treatment for GERD may fill gaps in inadequate surgical treatment. In April 2022, endoscopic anti-reflux mucosal resections (ARMS [anti-reflux mucosectomy] and ESD-G [endoscopic submucosal dissection for GERD]) were approved for reimbursement, making endoscopic treatment of GERD possible throughout Japan. KEY MESSAGES: It is important to identify the background factors in cases in which endoscopic treatments are effective.

Red Dichromatic Imaging Improves the Recognition of Bleeding Points During Endoscopic Submucosal Dissection.

BACKGROUND: Previous studies have indicated that red dichromatic imaging (RDI) improved the visibility of gastrointestinal bleeding. AIMS: To investigate the recognition of bleeding points during endoscopic submucosal dissection (ESD) under RDI compared with that under white light imaging (WLI). METHODS: Consecutive patients scheduled to undergo esophageal or gastric ESD at a single center were enrolled. Paired videos of active bleeding during ESD under WLI and RDI were created. Six endoscopists identified the virtual hemostasis point on still images after random video viewing. The distance between virtual hemostasis and actual bleeding points was scored in four levels (0-3 points), and the association with the color value was analyzed in both WLI and RDI. RESULTS: We evaluated 116 videos for 58 bleeding points. The median visibility score and recognition rate were significantly higher for RDI than for WLI (2.17 vs. 1.42, p < 0.001 and 62.1% vs 27.6%, p < 0.001). Additionally, the recognition rate of trainees in RDI was higher than that of experts in WLI (60.3% vs. 43.1%, p = 0.067). The median color difference of RDI was significantly higher than that of WLI (8.97 vs. 3.69, p < 0.001). Furthermore, the correlation coefficient between the visibility score and color difference was 0.712 (strong correlation). CONCLUSION: RDI can provide better recognition of bleeding points than WLI during ESD. Therefore, further studies are warranted to investigate whether RDI improves ESD outcomes.

Efficacy of Switching to Adalimumab for Maintenance of Remission Following Induction Therapy with Tacrolimus in Patients with Ulcerative Colitis.

BACKGROUND: Tacrolimus (TAC) effectively induces remission in refractory ulcerative colitis (UC). However, TAC therapy usually lasts for 3 months. Although azathioprine (AZA) is often used in maintenance therapy, the relapse rate remains high. Herein, we evaluated the efficacy of adalimumab (ADA) for remission maintenance in patients with UC after induction therapy with TAC. METHODS: We prospectively enrolled patients with moderate-to-severe UC who achieved clinical remission after 3 months of TAC therapy with endoscopic non-mucosal healing (Cohort A). After TAC discontinuation, the remission maintenance rate up to 1 year after starting ADA therapy was examined. We retrospectively enrolled patients with UC treated with TAC (Cohort B). Among patients in clinical remission after TAC treatment for 3 months, those who received AZA as remission maintenance therapy after TAC discontinuation constituted the AZA group. Patients in Cohort A who received ADA and AZA as remission maintenance therapy after TAC discontinuation constituted the ADA + AZA group. We compared the remission maintenance rates in the AZA and ADA + AZA groups for up to 5 years after TAC discontinuation. RESULTS: In Cohort A, of the 46 patients with UC treated with TAC, 17 were eligible for analysis after receiving ADA as remission maintenance therapy. A notable 88.2% (15/17) were still in remission 1 year after starting ADA. The ADA + AZA group (n = 16) exhibited a significantly higher relapse-free rate than the AZA group (n = 26) (p < 0.05; log-rank test). CONCLUSION: switching to ADA for remission maintenance in patients with refractory UC who achieved clinical remission with TAC is clinically useful.

Drug Delivery with Hyaluronic Acid-Coated Polymeric Micelles in Liver Fibrosis Therapy.

Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium is essential to establish a treatment for hepatic fibrosis. We previously developed hyaluronic acid (HA)-coated polymeric micelles that exhibited affinity to liver sinusoidal endothelial cells. HA-coated micelles possess a core-shell structure of self-assembled biodegradable poly(l-lysine)-b-poly(lactic acid) AB-diblock copolymer (PLys+-b-PLLA), and its exterior is coated with HA through polyion complex formation via electrostatic interaction between anionic HAs and cationic PLys segments. In this study, we prepared HA-coated micelles entrapping olmesartan medoxomil (OLM), an anti-fibrotic drug, and evaluated their possibility as drug delivery vehicles. HA-coated micelles exhibited specific cellular uptake into LX-2 cells (human HSC line) in vitro. In vivo imaging analysis after intravenous (i.v.) injection of HA-coated micelles into mice revealed that the micelles exhibited high accumulation in the liver. Observation of mouse liver tissue sections suggested that HA-coated micelles were distributed in liver tissue. Furthermore, i.v. injection of HA-coated micelles entrapping OLM showed a remarkable anti-fibrotic effect against the liver cirrhosis mouse model. Therefore, HA-coated micelles are promising candidates as drug delivery vehicles for the clinical management of liver fibrosis.

Relationship between Chemotherapy-Induced Diarrhea and Intestinal Microbiome Composition.

BACKGROUND AND AIM: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. METHODS: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. RESULTS: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. CONCLUSION: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

Examination on Factors Affecting Symptom Change after Drug Withdrawal in Patients with Mild Erosive Gastroesophageal Reflux Disease Undergoing Symptom-Controlled Maintenance Therapy with Acid-Secretion Inhibition Drugs.

INTRODUCTION: In patients with gastroesophageal reflux disease (GERD) on maintenance therapy with acid-suppressive drugs, it is not clear what background factors allow patients to discontinue the drugs. The aims of this study were to examine the relationship of the changes in the frequency and severity of gastrointestinal symptoms after discontinuation of acid-secretion inhibitors for erosive GERD (eGERD) with possible patient background factors and to identify factors that influence these changes. METHODS: This is a multicenter, open-label, interventional, exploratory study. eGERD patients with mild mucosal injury whose symptoms were under control and who were on maintenance therapy with acid-suppressive drugs were withdrawn from the drug treatment for 4 weeks. We examined the relationship of patient backgrounds (sex, age, body mass index, alcohol consumption, smoking habits), esophageal hiatal hernia, Helicobacter pylori infection, pepsinogen I and II concentrations and I/II ratios, blood gastrin levels before and after drug discontinuation with total score change in Frequency Scale for the Symptoms of GERD (FSSG). RESULTS: Of the 92 patients whose symptoms could be assessed before and after drug withdrawal, 66 patients (71.7% of the total) had FSSG <8 and no symptom relapse after the withdrawal. Furthermore, patient background factors that may be related to symptom relapse/non-relapse were examined, but no related factors were detected. The maintenance medications before discontinuation in the above 92 patients were a proton pump inhibitor (PPI) and vonoprazan (VPZ, a potassium ion competitive acid blocker). Since PPI and VPZ were administered to about the same number of patients, though incidentally, we additionally examined the relationship between patient background factors and symptom relapse/non-relapse by treatment group. As a result, no relevant background factors were detected in both groups. Although there were no significant differences between the two groups, the severity and frequency of symptom recurrence in the VPZ group tended to be higher than in the PPI group. CONCLUSIONS: Consideration of background factors is unlikely to be required in the discontinuation of maintenance therapy for eGERD. There was no significant difference in the extent of disease or frequency of recurrence during the discontinuation period, regardless of whether the drug before discontinuation was a PPI or VPZ.

Causal effect of anxiety and depression status on the symptoms of gastroesophageal reflux disease and functional dyspepsia during proton pump inhibitor therapy.

BACKGROUND: Although anxiety and depression status is considered related to gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) symptoms, ambiguity primarily arises from the difficulty in determining their cause-effect relationships. We aimed to examine the longitudinal reciprocal causation between anxiety/depression status and GERD/FD symptoms among symptomatic adult patients with GERD. METHODS: Adult (≥ 20 years) patients with GERD symptoms received PPI treatment for 4 weeks after endoscopy. GERD and FD symptom subscales (GERD-SS/FD-SS) were evaluated using the gastroesophageal reflux and dyspepsia therapeutic efficacy and satisfaction test (GERD-TEST). Anxiety and depression status were evaluated using the hospital anxiety and depression scale (HADS). A cross-lagged analysis using structural equation modeling was conducted to examine causal relationships among psychiatric bias (anxiety and depression scores) and upper gastrointestinal symptoms (GERD-SS and FD-SS scores) over time. RESULTS: A total of 182 patients with GERD (men: 120; age: 57.1 ± 12.8 years; body mass index: 24.2 ± 4.1 kg/m2; nonerosive reflux disease/erosive reflux disease: 61/121) were eligible before (T1) and after 4 weeks (T2) of PPI therapy. The cross-lagged effect model indicated that anxiety at T1 contributed to the FD-SS at T2 (ß = 0.18*) and depression at T1 contributed to the GERD-SS at T2 (ß = 0.23*) (*p < 0.05). CONCLUSION: Psychiatric bias was a risk factor for refractory GERD and FD. Anxiety and depression status reduced the therapeutic effect of PPIs on GERD and FD symptoms. Therefore, attention is required to detect the anxiety/depression status of patients with GERD/FD symptoms to treat patients appropriately and optimize therapeutic outcomes.

Clinical impact of recombinant thrombomodulin administration on disseminated intravascular coagulation due to severe acute cholangitis (Recover-AC study).

BACKGROUND AND AIM: Recombinant thrombomodulin (rhTM) is potentially effective in the treatment of disseminated intravascular coagulation (DIC). Several studies related to drugs for the treatment of acute cholangitis have shown negative results in improvement of overall survival (OS) with rhTM. The aim of this multicenter study was to evaluate the clinical effectiveness of rhTM in patients with acute cholangitis and sepsis-induced DIC who underwent biliary drainage. METHODS: A total of 284 consecutive patients, who were complicated with sepsis-induced DIC due to severe acute cholangitis, were included (rhTM group, n = 173; non-rhTM, n = 111) in this study. The primary outcome was the DIC resolution rate at 7 days after starting treatment. The 28-day survival rate was secondarily evaluated. RESULTS: DIC scores in the rhTM group improved significantly compared with the non-rhTM group on day 7 (P = .020). According to multivariate analysis, etiology of cholangitis (malignant, HR 2.28), rhTM (non-administration, HR 4.13), and DIC score (≥5, HR 2.46) were significant factors associated with failed DIC resolution on day 7. Propensity score matching created 103 matched pairs. Survival rate at day 28 was significantly higher in rhTM group (94.3%) compared with non-rhTM group (82.6%; P = .048) after propensity score matching. rhTM (non-administration, HR 2.870), DIC score (≥5, HR 2.751), and APACHE II score (≥20, HR 9.310) were significant factors associated with decreasing survival rate at day 28. CONCLUSION: In conclusion, rhTM seemed to improve patient survival, but future studies should only include patients with benign or malignant disease and should be performed according to APACHE II scores.

Prospective registration study of diagnostic yield and sample size in forceps biopsy using a novel device under digital cholangioscopy guidance with macroscopic on-site evaluation.

BACKGROUND: Although the SpyGlass Direct Visualization System can be clinically useful for diagnosing indeterminate biliary stricture, it employs SpyBite forceps, which typically obtain only a small amount of tissue and have a low sampling rate. An improved forceps biopsy device for SpyGlass DS has recently been released (SpyBite MAX). The aim of this prospective registration study was to assess the diagnostic yield and efficacy of histological biopsy tissue obtained with SpyBite MAX forceps compared with SpyBite forceps in patients with indeterminate biliary stricture. METHODS: The primary outcome of the study was the diagnostic accuracy of biopsy specimens obtained by SpyBite MAX forceps. The secondary outcomes were tissue size, number of forceps biopsies, rate of obtaining adequate tissue, and adverse events in the SpyBite MAX forceps group compared with the SpyBite group. RESULTS: Forceps biopsies using SpyBite MAX (n = 47) and SpyBite (n = 50) were performed successfully in all patients. The number of biopsies performed before visible core tissue was obtained was significantly lower in the SpyBite (mean, 1.5 ± 0.7) than in the SpyBite forceps group (mean, 2.3 ± 1.1 mm; P < .001). Tissue sample size was larger in the SpyBite MAX group (mean, 1.8 ± 1.6 mm2 ) than in the SpyBite group (mean, 1.0 ± 0.9 mm2 ; P = .004) but there was no significant difference in diagnostic accuracy. CONCLUSION: Improvements in dedicated forceps for biopsy in SpyGlass DS may contribute to improving the rates of adequate tissue and tissue sample size obtained, and to reducing the number of forceps biopsies required.

Comparison of the effects of individual symptoms of gastroesophageal reflux disease co-existing functional dyspepsia on patients' daily lives: A prospective, observational study.

Background and Aim: Patients with gastroesophageal reflux disease (GERD) frequently also have functional dyspepsia (FD) symptoms, which impair their quality of life. However, the magnitude and characteristics of the effects of each symptom on daily life have been unclarified. Using multiple regression analysis, we aimed to clarify these questions. Methods: We enrolled 290 patients from 29 institutions across Japan, in this prospective, observational study. Patients responded to three questionnaires (Gastroesophageal Reflux and Dyspepsia Therapeutic Efficacy and Satisfaction Test [GERD-TEST], Hospital Anxiety and Depression Scale [HADS], and 8-item Short-Form Health Survey [SF-8]) before and after 4 weeks of proton pump inhibitor treatment. Pearson correlation and multiple regression analyses were conducted between symptoms such as typical GERD, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) of FD, and aspects of daily life, namely, level of satisfaction with the daily life of GERD-TEST, anxiety and depression score of HADS, and physical and mental component summary of SF-8. Results: Pearson correlation analysis showed a significant correlation in all combinations between GERD/FD-EPS/FD-PDS symptoms and the nine aspects of daily life. However, multiple regression analysis results deviated from these results, with the most significant effects seen in the PDS-symptom subscale (SS) on the five aspects of daily life, that is, dissatisfaction with eating, daily life-SS, anxiety, depression, and mental component summary (MCS) whereas the significant effects in GERD-SS on five aspects of daily life, that is, dissatisfaction for eating, anxiety, depression, physical component summary, and MCS, disappeared. Conclusion: Dealing with co-existing FD symptoms without overlooking them may be important in the management of GERD.

Analysis of autonomic function during natural defecation in patients with irritable bowel syndrome using real-time recording with a wearable device.

BACKGROUND: Autonomic dysfunction is a factor in irritable bowel syndrome (IBS). However, there are no reports of autonomic nervous system (ANS) activity during natural defecation in patients with IBS. We aimed to clarify the relationship between ANS activity and life events, such as defecation and abdominal symptoms, using real-time recording. METHODS: Six patients with IBS and 14 healthy controls were enrolled in this prospective multicenter study. ANS activity was recorded for 24 h using a T-shirt wearable device, and life events were recorded simultaneously in real time using a smartphone application software. Low frequency/high frequency (LF/HF) and HF calculated by power spectrum analysis were defined as activity indicators of the sympathetic and parasympathetic nerves, respectively. RESULTS: The means of LF/HF and HF in the period with positive symptoms were comparable between the groups; however, the sum of LF/HF, sum of ΔLF/HF, and the maximum variation in ΔLF/HF were significantly higher in the IBS group. In the IBS group, the sum of ΔLF/HF and LF/HF increased significantly from 2 min before defecation, and the sum of LF/HF remained significantly higher until 9 min after defecation. The sum of ΔLF/HF at 2 min before defecation was significantly positively correlated with the intensity of abdominal pain and diarrhea and constipation scores. In contrast, it was significantly negatively correlated with defecation satisfaction and health-related quality of life. CONCLUSIONS: In patients with IBS, sympathetic nerve activity was activated 2 min before defecation, which was correlated with abdominal symptoms and lower QOL.

A Prospective Study Regarding the Efficacy and Safety of the BNT162b2 Vaccine in Patients With Solid Malignancies Undergoing Systemic Chemotherapy.

BACKGROUND/AIM: To prospectively evaluate the efficacy and safety of the BNT162b2 vaccine in solid cancer patients undergoing systemic chemotherapy (n=63). PATIENTS AND METHODS: COVID-19 anti-spike protein antibody levels were measured before the first BNT162b2 vaccination, just before the second BNT162b2 vaccination, one month after the second BNT162b2 vaccination, and 3 months after the second BNT162b2 vaccination. Anti-spike protein antibody seropositivity was set at ≥0.8 U/ml. RESULTS: Colorectal cancer was the most commonly observed primary disease (36.5%). ECOG-PS 0 was observed in the majority (52.4%) of patients. The overall response rate and the median (range) anti-spike protein antibody levels in the whole cohort at 3 months after the second BNT162b2 vaccination were 98.4% (62/63) and 206 (0.4-3,813) U/ml. None of the patients required postponement or discontinuation of systemic chemotherapy because of an adverse reaction. CONCLUSION: The BNT162b vaccine in solid cancer patients undergoing systemic chemotherapy is effective and safe.