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.

Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study.

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS: Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS: A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS: This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION: Clinical trial registration Japic CTI No.: JapicCTI-163380.  https://www. CLINICALTRIALS: jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .

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.

[Clinical Evaluation of the Efficacy and Adverse Effects of Nivolumab Treatment for Patients with Advanced Gastric Cancer].

BACKGROUND: Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1(PD-1), was approved for use in the treatment of patients with advanced gastric or gastroesophageal junction cancer who had been previously treated with B2 chemotherapy regimens in Japan. METHODS: We investigated the efficacy of nivolumab therapy in 15 consecutive patients with advanced gastric cancer between October 2017 and December 2018 in our facility. RESULTS: In our study, the 6-month overall survival rate was 67.7%, and the median survival time(MST)was 6.3 months. Immune-related adverse events(irAEs)occurred in the following patients: 2 patients, interstitial pneumonia(13%); 1 patient, myocarditis (6.7%); 1 patient, hypothyroidism(6.7%); and 1 patient, liver dysfunction(6.7%). Of the patients with an absolute lym- phocyte count(ALC)of C2,000/mL at baseline, 33%(4/12)experienced irAEs, while of those with an ALC of >2,000/mL, 67% had irAEs. The 6-month overall survival rate was better in patients with an ALC >1,600/mL(100%, 4/4)than in those with an ALC of C1,600/mL(35%, 4/11). The 6-month overall survival rate of the patients with a neutrophil-to-lymphocyte ratio(NLR)of <4 was 63%, which was better than the 33% rate in those with an NLR of B4. CONCLUSIONS: Nivolumab therapy was a safe and feasible treatment option. The cutoff values of ALC of 2,000/mL for irAEs and of ALC of 1,600/mL and NLR of 4 for prognosis might be effective surrogate markers in nivolumab treatment.

Efficacy and safety of Helicobacter pylori eradication therapy immediately after endoscopic submucosal dissection.

BACKGROUND AND AIMS: In the treatment of patients after endoscopic submucosal dissection (ESD), there is no consensus on the optimum time to start Helicobacter pylori eradication therapy or on whether eradication therapy improves ulcer healing rate after ESD. The aim of this study was to examine the effect of immediate eradication of H. pylori on ulcer healing after ESD in patients with early gastric neoplasms. METHODS: A total of 330 patients who underwent ESD for early gastric neoplasms were enrolled. Patients were assigned to either H. pylori eradication group (Group A: H. pylori eradication + proton pump inhibitor 7 weeks) or non-eradication group (Group B: proton pump inhibitor 8 weeks). The primary end point was gastric ulcer healing rate (Group A vs Group B) determined on week 8 after ESD. RESULTS: Patients in Group A failed to meet non-inferiority criteria for ulcer scarring rate after ESD compared with that in Group B (83.0% vs 86.5%, P for non-inferiority = 0.0599, 95% confidence interval: -11.7% to 4.7%). There were, however, neither large differences between the two groups in the ulcer scarring rate nor the safety profile. CONCLUSIONS: This study failed to demonstrate the non-inferiority of immediate H. pylori eradication therapy after ESD to the non-eradication therapy in the healing rate of ESD-caused ulcers. However, because the failure is likely to attribute to small number of patients enrolled, immediate eradication therapy may be a treatment option for patients after ESD without adverse effects on eradication therapy in comparison with the standard therapy.

Helicobacter pylori Eradication Therapy Ameliorates Latent Digestive Symptoms in Chronic Atrophic Gastritis.

BACKGROUND/AIMS: This study investigated the effect of Helicobacter pylori eradication therapy on latent digestive symptoms in chronic atrophic gastritis. METHODS: We enrolled 650 health checkup patients who underwent eradication therapy for chronic gastritis and completed a self-report questionnaire before and after the treatment between January 2014 and December 2016 at the Japanese Red Cross Society Kyoto Daiichi Hospital. RESULTS: H. pylori eradication therapy for chronic atrophic gastritis improved latent digestive symptoms, including both the acid reflux and dyspepsia components in the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) scores. The effect was sustained until 1 year after the treatment. Higher FSSG scores (≥8 points) before H. pylori eradication therapy and age <70 years were significantly associated with the improvement of digestive symptoms after H. pylori eradication therapy. CONCLUSION: H. pylori eradication therapy may improve patients' quality of life through the resolution of latent abdominal symptoms.

A case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema.

A 17-year-old boy developed prominent mediastinal and subcutaneous emphysema while receiving treatment with 5-aminosalicylic acid (5-ASA) and oral corticosteroids for severe ulcerative colitis. We ruled out infection and initiated oral administration of tacrolimus, after which both the underlying disease and mediastinal and subcutaneous emphysema improved. However, he continued to experience repeated bouts of ulcerative colitis, so we ultimately opted for surgical intervention. Although mediastinal and subcutaneous emphysema is rare, it is one of the known extra-intestinal complications and can be particularly concerning. In this patient, mediastinal and subcutaneous emphysema might have been caused by the vulnerability of pulmonary alveolar walls to steroid medication and the increase of pulmonary alveolar pressure with abdominal pain and breath holding. Here, we report a case of inflammatory bowel disease with mediastinal and subcutaneous emphysema, along with a review of the literature.

(68)Ga-DOTATOC-PET/CT for effective diagnosis and treatment of pancreatic tail gastrinoma with multiple liver metastases: a case report.

A 40-year-old man admitted to our hospital with diarrhea underwent abdominal computed tomography (CT) which showed multiple masses in the liver and pancreatic tail. Although there were no abnormal accumulations with fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET), (68)Ga-DOTATOC-PET/CT detected obvious abnormal accumulations for the both lobes of liver and pancreatic tail tumors. The serum gastrin was markedly high, and liver tumor biopsy demonstrated the presence of malignant cells with round nuclei that were positive for gastrin and somatostatin receptor. The patient was diagnosed with pancreatic tail gastrinoma with multiple liver metastases and treated with octreotide, everolimus, and a proton pump inhibitor which functionally controlled tumor growth. This case demonstrates (68)Ga-DOTATOC-PET/CT as a useful modality for the localization, qualitative diagnosis, and treatment of gastrinoma.

Defense mechanism of the esophageal mucosa against acid reflux.

In Japan, gastroesophageal reflux disease (GERD) follows a course of the increase with the change of the lifestyle. The pathogenesis of GERD is complicated, resulting from an imbal- ance between aggressive factors damaging the esophagus and a number of the natural defense mechanisms. It is important to understand the esophageal mucosal defense mecha- nism to understand the condition of GERD deeply. The esophageal mucosal protection con- sists of the presence of pre-epithelial, epithelial, and post-epithelial cellular and functional components including various tight junction proteins and nociceptors such as transient receptor potential vanilloid-1 (TRPV1). Recently, it has been suggested that visceral hyper- sensitivity associated with TRPV1 and substance P plays the important role to cause reflux symptoms.

[A case of freeze-dried gas gangrene antitoxin for the treatment of Clostridium perfringens sepsis].

A 66-year-old man was admitted to our hospital with high fever. We diagnosed a gas-containing liver abscess and performed percutaneous abscess drainage. However, 15 hours after admission, he developed massive intravascular hemolysis and acidosis. Sepsis due to Clostridium perfringens was suspected and we treated the patient intensively with multidisciplinary approaches, including antibiotics, mechanical ventilation, and renal replacement therapy. Furthermore, we administered freeze-dried gas gangrene antitoxin. Despite intensive care, the patient died 43 hours after admission.

A Case Report of Primary Neuroendocrine Carcinoma of the Anal Canal with Cancer Genome Profiling.

Primary neuroendocrine carcinoma (NEC) of the anal canal is a rare, highly malignant tumor with a poor prognosis. Despite the standard first-line treatment with etoposide or irinotecan combined with cisplatin, effective second-line therapies are lacking. In 2019, Japan approved cancer genome profiling (CGP) tests for solid tumors to enhance genomic understanding. We present the case of a 79-year-old woman with NEC of the anal canal, treated with etoposide, carboplatin, and amrubicin. Post-standard therapy, CGP suggested pemigatinib, a tyrosine kinase inhibitor; however, the patient died before receiving it. This case highlights the potential of personalized medicine to improve outcomes in such cases.

A large cell neuroendocrine carcinoma of the gall bladder: diagnosis with 18FDG-PET/CT-guided biliary cytology and treatment with combined chemotherapy achieved a long-term stable condition.

Poorly differentiated neuroendocrine cell carcinomas of the gallbladder are rare and patients with such tumors have a poor prognosis. We describe a 64-year-old male with a large cell neuroendocrine carcinoma of the gallbladder and multiple lymph node metastases. Diagnostic excisional biopsy of the left axillary lymph nodes revealed atypical cells with predominantly large-sized round-to-oval nuclei, proliferating in a solid and focal nesting pattern. The tumor cells were positive for synaptophysin and chromogranin A, and strongly positive for Ki-67, leading to a diagnosis of poorly differentiated neuroendocrine cell carcinoma of the gallbladder, of large cell type. Using (18)F-fluorodeoxy glucose-positron emission tomography/computed tomography to determine the origin of these tumors, we observed the accumulation of (18)F-fluorodeoxy glucose in multiple large lymph nodes, a small part of the liver and the fundus of the gallbladder. Computed tomography-guided aspiration of the gallbladder showed the same pleomorphic tumor cells as the lymph nodes. The patient was diagnosed with a large cell neuroendocrine carcinoma of the gallbladder, only ∼25 mm in diameter. Combination chemotherapy with cisplatin and docetaxel, the regimen used for non-small cell lung carcinomas, and probably large cell lung carcinomas, resulted in the disappearance of the lymph node metastases and a marked improvement in the performance status for ∼22 months. The poor prognosis of patients with these aggressive tumors may be improved by the use of minimally invasive diagnostic procedures and combined systemic chemotherapy as soon as possible.

Role of nociceptors/neuropeptides in the pathogenesis of visceral hypersensitivity of nonerosive reflux disease.

BACKGROUND AND AIMS: Esophageal visceral hypersensitivity has been proposed to be a pathogenesis of heartburn in nonerosive reflux disease (NERD), but its further mechanisms are unclear. Recently, it has been suggested that nociceptors and neuropeptides control sensory and pain mechanisms. Therefore, the objective of the present study was to estimate expression of acid-sensitive nociceptors such as transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3, protease-activated receptor 2 (PAR2), neuropeptides such as substance P and calcitonin-gene-related peptide, and their receptors such as neurokinin 1 receptor (NK1R) and receptor activity-modifying protein 1 in the esophageal mucosa of NERD patients. METHODS: Biopsy samples were taken from NERD patients and healthy control subjects without heartburn. The expression level of nociceptors, neuropeptides, and their receptors were assessed by real-time RT-PCR and enzyme immunoassay. Localization of substance P and CGRP in the esophageal mucosa was determined by immunohistochemical staining. RESULTS: Expression of mRNA for TRPV1 and PAR2 was significantly elevated in the esophageal mucosa of NERD patients. Substance P protein level and its receptor NK1R mRNA also increased in NERD patients. A positive correlation between the substance P protein level and reflux symptoms was observed. Immunohistochemical study revealed the presence of substance P-positive nerves in the lamina propria of the esophagus. CONCLUSIONS: These findings suggest that visceral hypersensitivity in NERD patients is involved in neurogenic inflammation showing the increase in both substance P release and NK1R expression, which may be associated with the activation of TRPV1 and PAR2.

Changes in endoscopic findings of gastritis after cure of H. pylori infection: multicenter prospective trial.

BACKGROUND AND AIM: Successful eradication of H. pylori changes pathological findings of gastritis dramatically. However, change of endoscopic mucosal findings is not fully understood. To clarify the short-term changes of endoscopic mucosal findings after cure of H. pylori infection, a multicenter prospective trial was conducted. METHODS: One hundred and forty-seven patients with H. pylori infection from 12 institutions were enrolled into this prospective cohort trial. Nineteen endoscopic findings using high-resolution white light electronic endoscopy were assessed before and 2-4 months after eradication treatment of H. pylori. H. pylori infection was diagnosed by pathology of three stomach sites using hematoxylin-eosin stain or H. pylori-specific immunostaining. Endoscopic features of the successful eradication group and the failed eradication group were compared. The change of severity of endoscopic features before and after H. pylori eradication were compared between successful eradication and failed eradication. RESULTS: One hundred and twenty-six patients were analyzed. Eradication rate was 81% (102/126). Non-transparency of gastric juice, diffuse redness of fundic mucosa, enlarged fold, spotty redness of fundic mucosa, flat erosion of stomach, and hemoglobin index of fundic mucosa were significantly different between the successful eradication group and the failed eradication group. Gastric flat erosion was of higher frequency in the successful eradication group. When eradication was successful, spotty redness of fundic gland improved significantly. CONCLUSION: Assessment of endoscopic findings of spotty redness after eradication treatment is useful in the diagnosis of H. pylori eradication.

A Smartphone Application and Education Program for Hearing Health Promotion in High School Teenagers.

OBJECTIVES: To assess knowledge retention after video-based hearing health education and measure headphone listening behavior change using a novel smartphone application. METHODS: In this prospective longitudinal study, students participated in video-based hearing health education and hearing screening sessions. Hearing health knowledge was assessed in students and parents after 6 weeks. A novel smartphone application was created to measure daily noise exposure based on volume settings with headphone use and to display the National Institute for Occupational Safety and Health (NIOSH) noise doses with alerts for cumulative daily doses nearing the maximum. RESULTS: Seventy-six teenage students and parents participated. Eighty three percent of participants identified as a racial or ethnic minority and 66% were of low-income socioeconomic status. Hearing health knowledge was retained in students 6 weeks after education and parents' knowledge improved from baseline. The smartphone app was installed on 12 student phones, and 25% of days monitored exhibited noise doses that exceeded the NIOSH maximum. App use for at least 10 days by nine students showed a significant reduction in average daily noise dose and time spent at the highest volume settings during the second-half of app use. CONCLUSIONS: Video-based hearing health education with knowledge question reinforcement was associated with knowledge retention in students and improved parental attitudes and knowledge about hearing conservation. A smartphone app with a real-time display of headphone cumulative noise exposure dose identified at-risk students. The integration of hearing health education, hearing screening, and digital health tools has promised to promote positive behavior changes for long-term hearing conservation. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2007-2013, 2023.

Endoscopic submucosal dissection for undifferentiated early gastric cancer as the expanded indication lesion.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become the standard endoscopic treatment for early gastric cancer without lymph node metastasis. At present, undifferentiated type intramucosal cancers without ulcer findings <20 mm in size are often chosen as endoscopic treatment lesions for expanded indication. The purpose of this study was to examine the outcome of ESD treatment in undifferentiated carcinomas. METHOD: Forty-six patients who had undergone ESD from July 2002 until July 2010, where the final pathological diagnosis was undifferentiated carcinoma, were assessed for the en-bloc resection ratio, the accuracy rate of depth or extent of diagnosis and survival. RESULTS: In endoscopic ultrasonography studies, the accuracy rate of mucosal lesions was 86%. The rate of en-bloc resection was 91% (42/46) and 5 cases had a positive margin. Four cases had a positive margin in cases of piecemeal resection. Five cases underwent additional surgery, and residual cancer was found in 1 case. There were 2 cases of perforation, 2 of delayed hemorrhage, and no cases of delayed perforation. One case died of multiple liver metastases and 1 died of hepatocellular carcinoma. After a maximum of 8 years, an average of 3.8 years of observation, including 7 cases who had undergone additional surgery, recurrence occurred in only 1 case of liver metastasis. CONCLUSION: In this study the lesions of undifferentiated adenocarcinoma, which were limited to the mucosa, <20 mm in diameter and had been completely resected, showed no recurrence and were indicated for endoscopic treatment.

[Staphylococcal food poisoning and MRSA enterocolitis].

Staphylococcal food poisoning is a gastrointestinal illness. It is caused by eating foods contaminated with enterotoxins produced by Staphylococcus aureus. The enterotoxins are fast acting, sometimes causing illness within one to six hours. Patients typically experience nausea, vomiting, stomach cramps, and diarrhea. Diagnosis of staphylococcal food poisoning is generally based only on the symptoms of patients. The treatments for these patients are rest and plenty of fluids. Antibiotics are not useful in treating this illness. On the other hand, methicillin resistant Staphylococcus aureus (MRSA) enteritis and colitis caused by microbial substitution with administration of antibiotics is aggressive and sick with severe diarrhea. The treatment of those patients are as follows; antibiotics now in use are stopped and oral administration of vancomycin is started as soon as possible.

Oxidative stress-induced posttranslational modification of TRPV1 expressed in esophageal epithelial cells.

Human esophageal epithelium is continuously exposed to physical stimuli or to gastric acid that sometimes causes inflammation of the mucosa. Transient receptor potential vanilloid 1 (TRPV1) is a nociceptive, Ca(2+)-selective ion channel activated by capsaicin, heat, and protons. It has been reported that activation of TRPV1 expressed in esophageal mucosa is involved in gastroesophageal reflux disease (GERD) or in nonerosive GERD symptoms. In this study, we examined the expression and function of TRPV1 in the human esophageal epithelial cell line Het1A, focusing in particular on the role of oxidative stress. Interleukin-8 (IL-8) secreted by Het1A cells upon stimulation by capsaicin or acid with/without 4-hydroxy-2-nonenal (HNE) was measured by ELISA. Following capsaicin stimulation, the intracellular production of reactive oxygen species (ROS) was determined using a redox-sensitive fluorogenic probe, and ROS- and HNE-modified proteins were determined by Western blotting using biotinylated cysteine and anti-HNE antibody, respectively. HNE modification of TRPV1 proteins was further investigated by immunoprecipitation after treatment with synthetic HNE. Capsaicin and acid induced IL-8 production in Het1A cells, and this production was diminished by antagonists of TRPV1. Capsaicin also significantly increased the production of intracellular ROS and ROS- or HNE-modified proteins in Het1A cells. Moreover, IL-8 production in capsaicin-stimulated Het1A cells was enhanced by synthetic HNE treatment. Immunoprecipitation studies revealed that TRPV1 was modified by HNE in synthetic HNE-stimulated Het1A cells. We concluded that TRPV1 functions in chemokine production in esophageal epithelial cells, and this function may be regulated by ROS via posttranslational modification of TRPV1.

[A case of recurrent lymph node metastases of advanced colon cancer with penetration of the gastric wall, treated effectively by cetuximab monotherapy as third-line treatment].

A 45-year-old man was first treated for lymph node metastases of colon cancer with FOLFIRI. After 13 courses, the lymph node metastases worsened, and he was treated with mFOLFOX6 plus bevacizumab as the second-line chemotherapy. After 8 courses, his anorexia and anemia became increasingly troublesome. We diagnosed this as the direct invasion of lymph node metastases to the gastric wall. As the third-line chemotherapy, cetuximab monotherapy was applied. The gastric ulcer lesion then began healing as a scar. In our progressive case, cetuximab monotherapy was effective as a third-line treatment.