Necessity of pharyngeal anesthesia during transoral gastrointestinal endoscopy: a randomized clinical trial.

BACKGROUND/AIMS: The necessity for pharyngeal anesthesia during upper gastrointestinal endoscopy is controversial. This study aimed to compare the observation ability with and without pharyngeal anesthesia under midazolam sedation. METHODS: This prospective, single-blinded, randomized study included 500 patients who underwent transoral upper gastrointestinal endoscopy under intravenous midazolam sedation. Patients were randomly allocated to pharyngeal anesthesia: PA+ or PA- groups (250 patients/group). The endoscopists obtained 10 images of the oropharynx and hypopharynx. The primary outcome was the non-inferiority of the PA- group in terms of the pharyngeal observation success rate. RESULTS: The pharyngeal observation success rates in the pharyngeal anesthesia with and without (PA+ and PA-) groups were 84.0% and 72.0%, respectively. The PA- group was inferior (p=0.707, non-inferiority) to the PA+ group in terms of observable parts (8.33 vs. 8.86, p=0.006), time (67.2 vs. 58.2 seconds, p=0.001), and pain (1.21±2.37 vs. 0.68±1.78, p=0.004, 0-10 point visual analog scale). Suitable quality images of the posterior wall of the oropharynx, vocal fold, and pyriform sinus were inferior in the PA- group. Subgroup analysis showed a higher sedation level (Ramsay score ≥5) with almost no differences in the pharyngeal observation success rate between the groups. CONCLUSION: Non-pharyngeal anesthesia showed no non-inferiority in pharyngeal observation ability. Pharyngeal anesthesia may improve pharyngeal observation ability in the hypopharynx and reduce pain. However, deeper anesthesia may reduce this difference.

Patient-derived Enterococcus faecium with inflammatory genotypes promote colitis.

BACKGROUND: Dysbiosis of gut microbiota promotes colitis in ulcerative colitis (UC). Enterococcus faecium is an important constituent of dysbiotic microbiota. However, the mechanisms underlying E. faecium-induced colitis remain unclear. METHODS: Overall, 23 E. faecium strains isolated from human feces and 3 commercial strains were inoculated into Il10-/- mice. Mouse colons were histologically evaluated and analyzed using real-time PCR analysis of cytokines. Genes in 26 E. faecium strains were identified by whole-genome shotgun sequencing of genomic DNA. The production of reactive oxygen species (ROS) from each strain was measured. An antioxidant, lipoic acid, was orally administered to the colitis mouse model. RESULTS: Inoculation of E. faecium derived from patients with UC resulted in colitis in Il10-/- mice. The genotypes of 26 strains were characterized by identifying 1893 known genes; clustering all the strains based on the genotypes showed two major groups-inflammatory and probiotic clusters. Additionally, linear discriminant analysis clarified that lipoic acid metabolism was a significantly abundant pathway in the probiotic cluster compared to the inflammatory cluster. Further, the production of ROS was greater in inflammatory than in probiotic strains. Administration of lipoic acid in E. faecium-inoculated mice ameliorated colitis. CONCLUSIONS: Enterococcus faecium strains in the inflammatory cluster promoted colitis with higher production of ROS than the strains in the probiotic cluster.

Oral Corticosteroids Impair Mucin Production and Alter the Posttransplantation Microbiota in the Gut.

INTRODUCTION: Gut microbiota alterations cause inflammation in patients with ulcerative colitis (UC). Fecal microbiota transplantation (FMT) enables manipulating the microbiota's composition, but the mechanisms underlying colonization of the posttransplantation microbiota are poorly understood. METHODS: In this open-label, nonrandomized study, the FMT efficacy and changes in the gut microbiota were evaluated in 8 UC patients with mild-to-moderately active endoscopic colonic lesions. Compositional changes in the fecal and mucosal microbiotas between donors and recipients were examined via 16S rRNA-based sequencing. To investigate the effects of oral corticosteroids on microbiota colonization, FMT was performed in germ-free prednisolone (PSL)-administered mice to examine the factors determining colonization. RESULTS: Four UC patients achieved clinical remission (CR) after FMT, and 3 also achieved endoscopic remission. The fecal microbiotas of the CR patients changed similar to those of the donors after FMT. The mucin-coding gene, MUC2, was less expressed in the colons of the PSL-dependent patients than in the PSL-free patients. In the mice, PSL treatment decreased the fecal mucin production and altered the posttransplantation fecal microbiota composition. Adding either exogenous mucin or the mucin secretagogue, rebamipide, partially alleviated the PSL-induced dysbiosis of the gut microbiota. Administering rebamipide with FMT from healthy donors relieved inflammation in mice with Enterococcus faecium-induced colitis. CONCLUSION: Colonic mucin controlled the gut microbiota composition, and oral corticosteroid treatment modified the gut microbiota partly by reducing the colonic mucin.

Dysbiotic gut microbiota in pancreatic cancer patients form correlation networks with the oral microbiota and prognostic factors.

Microbiota in the gut and oral cavities of pancreatic cancer (PC) patients differ from those of healthy persons, and bacteria in PC tissues are associated with patients' prognoses. However, the species-level relationship between a dysbiotic gut, oral and cancerous microbiota, and prognostic factors remains unknown. Whole-genome sequencing was performed with fecal DNA from 24 PC patients and 18 healthy persons (HD). Microbial taxonomies, metabolic pathways, and viral presence were determined. DNA was sequenced from saliva and PC tissues, and the association between the gut, oral, and cancer microbiota and prognostic factors in PC patients was analyzed. The PC microbiota were altered from those of the healthy microbiota in terms of microbial taxonomy, pathways and viral presence. Twenty-six species differed significantly between the PC and HD microbiota. Six fecal microbes, including Klebsiella pneumoniae, were associated with an increased hazard of death. In the co-occurrence network, microbes that were abundant in PC patients were plotted close together and formed clusters with prognosis-associated microbes, including K. pneumoniae. Multiple salivary microbes were present in the co-occurrence network. Microbacterium and Stenotrophomonas were detected in the PC tissues and formed a network with the fecal and salivary microbes. The dysbiotic gut microbiota in the PC patients formed a complex network with the oral and cancerous microbiota, and gut microbes abundant in the PC patients were closely linked with poor prognostic factors in the network.

Chronic liver disease enables gut Enterococcus faecalis colonization to promote liver carcinogenesis.

Gut dysbiosis is observed in chronic hepatobiliary diseases and is frequently associated with liver carcinogenesis; however, the extent and specific mechanisms triggered by alterations in the microbiota mediating tumorigenesis in these patients remain unclear. Here we show that Enterococcus faecalis is abundant in the microbiota of patients with hepatitis C virus-related chronic liver disease. Xenotransplantation of gut microbiota from these patients increased the number of spontaneous liver tumors in mice and enhanced susceptibility to liver carcinogens. Hepatic colonization by gelE-positive E. faecalis increased liver expression of proliferative genes in a TLR4-Myd88-dependent manner, leading to liver tumorigenesis. Moreover, decreased fecal deoxycholic acid levels were associated with colonization by E. faecalis. Overall, these data identify E. faecalis as a key promoter of liver carcinogenesis.

Gut-derived Enterococcus faecium from ulcerative colitis patients promotes colitis in a genetically susceptible mouse host.

BACKGROUND: Recent metagenomic analyses have revealed dysbiosis of the gut microbiota of ulcerative colitis (UC) patients. However, the impacts of this dysbiosis are not fully understood, particularly at the strain level. RESULTS: We perform whole-genome shotgun sequencing of fecal DNA extracts from 13 healthy donors and 16 UC and 8 Crohn's disease (CD) patients. The microbiota of UC and CD patients is taxonomically and functionally divergent from that of healthy donors, with E. faecium being the most differentially abundant species between the two microbial communities. Transplantation of feces from UC or CD patients into Il10-/- mice promotes pathological inflammation and cytokine expression in the mouse colon, although distinct cytokine expression profiles are observed between UC and CD. Unlike isolates derived from healthy donors, E. faecium isolates from the feces of UC patients, along with E. faecium strain ATCC 19434, promotes colitis and colonic cytokine expression. Inflammatory E. faecium strains, including ATCC 19434 and a UC-derived strain, cluster separately from commercially available probiotic strains based on whole-genome shotgun sequencing analysis. The presence of E. faecium in fecal samples is associated with large disease extent and the need for multiple medications in UC patients. CONCLUSIONS: E. faecium strains derived from UC patients display an inflammatory genotype that causes colitis.

Overuse of antianaerobic drug is associated with poor postchemotherapy prognosis of patients with hepatocellular carcinoma.

Overuse of antibiotic drugs alters the composition of gut microbiota and has detrimental effects on the host. In our study, we investigated association of gut flora and antibiotics in the prognosis of patients with liver cancer who have undergone chemotherapy by analyzing two independent clinical studies. We retrospectively subanalyzed a previously reported randomized controlled trial (RCT) on hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma (HCC) to investigate the association between use of antibiotics and prognosis. In the other study, we prospectively determined the abundance of specific bacterial genus in patients with HCC by sequencing 16S ribosomal RNA and assessed its association with survival. Subanalysis of the RCT data showed that, of 26 types of antibiotics used, administration of carbapenem before or during chemotherapy was associated with poor progression-free survival (PFS) and overall survival (OS) of patients with HCC (carbapenem + vs. -; median PFS, 78 days vs. 154 days, p = 0.0053; median OS, 177 days vs. 475 days, p = 0.0003). Multivariate analysis revealed that antianaerobic drug use is an independent predictor of poor prognosis. In the prospective study, the abundance of Blautia in fecal microbiota correlated positively with both PFS and OS of patients with HCC who underwent chemotherapy. Use of antibiotics targeting anaerobes is associated with a poor prognosis in patients with HCC who have undergone chemotherapy, whereas the intestinal anaerobic bacteria, Blautia is associated with a good prognosis. These findings might indicate the need for caution regarding overuse of broad-spectrum antibiotics targeting anaerobes in patients with HCC.

Cytomegalovirus Reactivation Induced Acute Hepatitis and Gastric Erosions in a Patient with Rheumatoid Arthritis under Treatment with an Anti-IL-6 Receptor Antibody, Tocilizumab.

Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.

Clinical utility of endoscopic ultrasound-guided fine-needle aspiration in mixed adenoneuroendocrine carcinoma with signet-ring cells of the pancreas: a case report and review of the literature.

A man in his 60s visited our hospital because of a pancreatic head tumor. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed that the tumor consisted of a neuroendocrine carcinoma (NEC) and adenocarcinoma, including signet-ring cell carcinoma, and that the ratio of these components was approximately 50:50. Therefore, he was diagnosed with mixed adenoneuroendocrine carcinoma (MANEC). Because of liver and lymph node metastases, systemic chemotherapy was initiated using a regimen for the NEC component based on an increase in neuron-specific enolase (NSE). Although the patient achieved stable disease after two chemotherapy cycles, the tumor increased in size after three cycles, which was associated with a gradual increase in carcinoembryonic antigen and a decrease in NSE level. An EUS-FNA reexamination revealed that the adenocarcinoma component accounted for 90 % of the tumor. Thus, an adenocarcinoma chemotherapy regimen was started, and a slight reduction in tumor size was observed. Here, we report an extremely rare and remarkable case of MANEC of the pancreas that demonstrates the effectiveness of EUS-FNA for helping to decide the chemotherapy regimen.

[A case of Wilson's disease in an elderly patient initially diagnosed with NASH].

A 62-year-old female was admitted to our hospital for examination of icterus and thrombocytopenia. She had a history of diabetes mellitus (under treatment), and liver cirrhosis was evident on abdominal CT. Because she was clinically obese and had no past history of alcohol consumption, the initial diagnosis was NASH. However, subsequent MRI findings and normal serum transaminase levels were not consistent with this diagnosis. We then performed additional examinations, including liver biopsy, measurements of serum Cu and ceruloplasmin concentrations, and measurement of urinary Cu secretion, which resulted in a diagnosis of Wilson's disease. It is necessary to include Wilson's disease in the differential diagnosis of NASH in cases of unidentified liver disease even among elderly patients.