Mathematical theory of Bayesian statistics for unknown information source.

In statistical inference, uncertainty is unknown and all models are wrong. That is to say, a person who makes a statistical model and a prior distribution is simultaneously aware that both are fictional candidates. To study such cases, statistical measures have been constructed, such as cross validation, information criteria and marginal likelihood; however, their mathematical properties have not yet been completely clarified when statistical models are under- or over-parametrized. We introduce a place of mathematical theory of Bayesian statistics for unknown uncertainty, which clarifies general properties of cross validation, information criteria and marginal likelihood, even if an unknown data-generating process is unrealizable by a model or even if the posterior distribution cannot be approximated by any normal distribution. Hence it gives a helpful standpoint for a person who cannot believe in any specific model and prior. This paper consists of three parts. The first is a new result, whereas the second and third are well-known previous results with new experiments. We show there exists a more precise estimator of the generalization loss than leave-one-out cross validation, there exists a more accurate approximation of marginal likelihood than Bayesian information criterion, and the optimal hyperparameters for generalization loss and marginal likelihood are different. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.

The Inhibitory Effects of Anti-ERC/Mesothelin Antibody 22A31 on Colorectal Adenocarcinoma Cells, within a Mouse Xenograft Model.

The expression of Renal Carcinoma (ERC)/mesothelin is enhanced in a variety of cancers. ERC/mesothelin contributes to cancer progression by modulating cell signals that regulate proliferation and apoptosis. Based on such biological insights, ERC/mesothelin has become a molecular target for the treatment of mesothelioma, pancreatic cancer, and ovarian cancer. Recent studies revealed about 50-60% of colorectal adenocarcinomas also express ERC/mesothelin. Therefore, colorectal cancer can also be a potential target of the treatment using an anti-ERC/mesothelin antibody. We previously demonstrated an anti-tumor effect of anti-ERC antibody 22A31 against mesothelioma. In this study, we investigated the effect of 22A31 on a colorectal adenocarcinoma cell line, HCT116. The cells were xenografted into BALB/c nu/nu mice. All mice were randomly allocated to either an antibody treatment group with 22A31 or isotype-matched control IgG1κ. We compared the volume of subsequent tumors, and tumors were pathologically assessed by immunohistochemistry. Tumors treated with 22A31 were significantly smaller than those treated with IgG1κ and contained significantly fewer mitotic cells with Ki67 staining. We demonstrated that 22A31 exhibited a growth inhibitory property on HCT116. Our results implied that ERC/mesothelin-targeted therapy might be a promising treatment for colorectal cancer.

Autophagic dysfunction in the liver enhances the expression of insoluble nuclear proteins 14-3-3ζ and importin α4.

AIMS: Autophagic dysfunction is associated with the progression of various liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, serum markers for evaluating autophagic function have not been reported. Highly insoluble nuclear proteins participate in many cellular functions and are potential diagnostic markers for cancer. We performed a proteomic analysis of the hepatic nuclear insoluble fraction to identify novel autophagy-related diagnostic biomarkers. MAIN METHODS: The insoluble nuclear protein fraction was extracted from the livers of Atg7F/F, Atg7F/F:alb-Cre (hepatocyte-specific autophagy-deficient mice), C57BL/6 J, and KKAy (NAFLD model) mice. Proteins were separated by two-dimensional electrophoresis and visualized by silver staining. Protein spots were identified using mass spectrometry. The localization of proteins in hepatocytes was verified by immunofluorescence using a confocal microscope. KEY FINDINGS: The levels of insoluble nuclear proteins 14-3-3ζ and importin α4 were upregulated following hepatic autophagy dysfunction and were detectable in serum. Under normal conditions, these proteins are mainly distributed in the cytoplasm, whereas autophagic dysfunction induces their translocation to the nucleus. Incubation with an autophagy inhibitor up-regulated these proteins expression in the insoluble nuclear fraction of primary hepatocytes. Treatment with EGF or insulin enhanced 14-3-3ζ expression in the nuclear insoluble fraction; in contrast, the addition of rapamycin downregulated 14-3-3ζ expression. Importin α4 expression was increased in the nuclear insoluble fraction after incubation with tunicamycin or hydrogen peroxide. SIGNIFICANCE: Accumulation of 14-3-3ζ and importin α4 as nuclear-insoluble proteins may be associated with autophagic dysfunction. Our findings indicate that these proteins might be useful diagnostic biomarkers for liver diseases with autophagic disorders.

Relief Effect of Carbon Dioxide Insufflation in Transnasal Endoscopy for Health Checks-A Prospective, Double-Blind, Case-Control Trial.

CO2 insufflation has proven effective in reducing patients' pain after colonoscopies but has not been examined in esophagogastroduodenoscopies. Therefore, we examined the effect of CO2 insufflation in examinees who underwent transnasal endoscopies without sedation. This study is a single-center, prospective, double-blind, case-control trial conducted between March 2017 and August 2018. Subjects were assigned weekly to receive insufflation with either CO2 or air. The primary outcome was improvement of abdominal pain and distension at 2 h and 1-day postprocedure. In total, 336 and 338 examinees were assigned to the CO2 and air groups, respectively. Visual analog scale (VAS) scores for abdominal distension (15.4 vs. 25.5; p < 0.001) and distress from flatus (16.0 vs. 28.8; p < 0.001) at 2 h postprocedure were significantly reduced in the CO2 group. VAS scores for pain during the procedure (33.5 vs. 37.1; p = 0.059) and abdominal pain after the procedure (3.9 vs. 5.7; p = 0.052) also tended to be lower at 2 h postprocedure, but all parameters showed no significant difference at 1-day postprocedure. All procedures were safely completed through the planned program, and no apparent adverse events requiring treatment or follow-up occurred. In conclusion, CO2 insufflation may reduce postprocedural abdominal discomfort from transnasal esophagogastroduodenoscopies. (UMIN000028543).

Gender-specific development of experimental autoimmune cholangitis induced by double-stranded RNA.

Here we investigated the gender difference in murine cholangitis resembling human primary biliary cholangitis (PBC) caused by synthetic double-stranded RNA, and underlying hepatic innate immune responses. Female C57Bl/6 mice given repeated injections of polyinosinic-polycytidylic acid (poly I:C) for 24 weeks developed overt cholangitis with positive serum anti-mitochondria-M2 antibody, whereas male mice showed minimal pathological changes without induction in autoantibody. Poly I:C induced hepatic inflammatory cytokines and type-I interferons predominantly in females. Hepatic expression levels of toll-like receptor (TLR) 3 and melanoma differentiation-associated protein (MDA) 5 were equivalent in both genders; however, both mRNA and protein levels of retinoic acid-inducible gene (RIG)-I were nearly doubled in female livers. Following 4-week injections of poly I:C, not only hepatic RIG-I, but also TLR3 and MDA5 showed female-predominance. Moreover, hepatic RIG-I levels were 25% lower in ovariectomized mice, whereas supplementation of 17 ß-estradiol enhanced hepatic RIG-I expression, as well as cytokine induction. These results clearly indicate that hepatic RIG-I expression is potentiated by estrogen, and triggers gender-dependent hepatic innate immune response against double-stranded RNA, which most likely play a pivotal role in the pathogenesis of autoimmune cholangiopathies including PBC.

Gastric epithelial neoplasm of fundic-gland mucosa lineage: proposal for a new classification in association with gastric adenocarcinoma of fundic-gland type.

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. METHODS: One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. RESULTS: GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. CONCLUSIONS: We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

Evidence-based clinical practice guidelines for peptic ulcer disease 2020.

The Japanese Society of Gastroenterology (JSGE) revised the third edition of evidence-based clinical practice guidelines for peptic ulcer disease in 2020 and created an English version. The revised guidelines consist of nine items: epidemiology, hemorrhagic gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcers, non-H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Therapeutic algorithms for the treatment of peptic ulcers differ based on ulcer complications. In patients with NSAID-induced ulcers, NSAIDs are discontinued and anti-ulcer therapy is administered. If NSAIDs cannot be discontinued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recommended as the first-line treatment for H. pylori eradication, and PPIs or VPZ with antibiotics is recommended as a second-line therapy. Patients who do not use NSAIDs and are H. pylori negative are considered to have idiopathic peptic ulcers. Algorithms for the prevention of NSAID- and low-dose aspirin (LDA)-related ulcers are presented in this guideline. These algorithms differ based on the concomitant use of LDA or NSAIDs and ulcer history or hemorrhagic ulcer history. In patients with a history of ulcers receiving NSAID therapy, PPIs with or without celecoxib are recommended and the administration of VPZ is suggested for the prevention of ulcer recurrence. In patients with a history of ulcers receiving LDA therapy, PPIs or VPZ are recommended and the administration of a histamine 2-receptor antagonist is suggested for the prevention of ulcer recurrence.

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. METHODS: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. RESULTS: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. CONCLUSION: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

A Soluble Fiber Diet Increases Bacteroides fragilis Group Abundance and Immunoglobulin A Production in the Gut.

Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Previous studies have shown that Bacteroidetes, the major phylum of gut microbiota together with Firmicutes, impact IgA production. However, the relative abundances of species of Bacteroidetes responsible for IgA production were not well understood. In the present study, we identified some specific Bacteroidetes species that were associated with gut IgA induction by hsp60-based profiling of species distribution among Bacteroidetes The levels of IgA and the expression of the gene encoding activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were increased in soluble high-fiber diet (sHFD)-fed mice. We found that Bacteroides acidifaciens was the most abundant Bacteroidetes species in both sHFD- and normal diet-fed mice. In addition, the gut IgA levels were associated with the relative abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciens Conversely, the ratio of B. acidifaciens to other Bacteroidetes species was reduced in insoluble high-fiber diet fed- and no-fiber diet-fed mice. To investigate whether B. acidifaciens increases IgA production, we generated B. acidifaciens monoassociated mice and found increased gut IgA production and AID expression. Collectively, soluble dietary fiber increases the ratio of gut Bacteroides fragilis group, such as B. acidifaciens, and IgA production. This might improve gut immune function, thereby protecting against bowel pathogens and reducing the incidence of inflammatory bowel diseases.IMPORTANCE Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Gut microbiota impact IgA production, but the specific species responsible for IgA production remain largely elusive. Previous studies have shown that IgA and Bacteroidetes, the major phyla of gut microbiota, were increased in soluble high-fiber diet-fed mice. We show here that the levels of IgA in the gut and the expression of activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were correlated with the abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciensB. acidifaciens monoassociated mice increased gut IgA production and AID expression. Soluble dietary fiber may improve gut immune function, thereby protecting against bowel pathogens and reducing inflammatory bowel diseases.

Impact of maternal dietary gut microbial metabolites on an offspring's systemic immune response in mouse models.

The gut microbiota has a great impact on the host immune systems. Recent evidence suggests that the maternal gut microbiota affects the immune systems of offspring. Metabolites produced by the gut microbiota play crucial roles in the immune system. Previous studies have also revealed that metabolites such as short-chain fatty acids (SCFAs) and the aryl hydrocarbon receptor (AhR) ligands are involved in host health and diseases. Great progress has been made in understanding the roles of diet-derived SCFAs in the offspring's immune system. The findings to date raise the possibility that maternal dietary soluble fiber intake may play a role in the development of the offspring's systemic immune response. In this review, we summarize the present knowledge and discuss future therapeutic possibilities for using dietary soluble fiber intake against inflammatory diseases.

Frequent loss of heterozygosity of SMAD4 locus and prognostic impacts of SMAD4 immunohistochemistry in gastric adenocarcinoma with enteroblastic differentiation.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of gastric adenocarcinoma. Clinicopathologically, GAED is known to be aggressive and is characterized by frequent vascular invasion, lymphatic invasion, and liver metastasis even in early stages. SMAD4 was identified as a frequently deleted gene in GAED by copy number variation analysis in our previous next-generation sequencing study; therefore, we examined the clinicopathological impacts of SMAD4 in 51 cases of GAEDs (early: 17, advanced: 34). We performed Sanger sequencing for SMAD4 mutations and loss of heterozygosity (LOH) analysis of the SMAD4 locus, in addition to immunohistochemistry for SMAD4, to determine its clinicopathological correlations and impacts on survival. The frequency of LOH at the SMAD4 locus was 45.1%, and it was significantly higher in GAED compared to in conventional gastric adenocarcinoma. SMAD4 mutations were not found in any case. Reduced SMAD4 expression was found in 60.8% of cases; it was significantly correlated with advanced stages and lymph node metastasis and showed trends of larger tumor size and lymphatic invasion. Reduced SMAD4 expression in metastatic lymph nodes was found in 21 of 36 cases. Survival analysis revealed that reduced SMAD4 expression significantly affected the patient's overall survival (OS) and recurrence-free survival (RFS), although multivariate analysis showed that only liver metastasis and lymphatic infiltration (Ly+) were independent prognostic factors for OS and RFS. The SMAD4 locus is one of the susceptibility genes in this tumor, although SMAD4 mutation was not detected. Furthermore, the inactivation of SMAD4 appeared to contribute to the aggressiveness of GAED.

A prospective randomized trial of a potassium competitive acid blocker vs proton pump inhibitors on the effect of ulcer healing after endoscopic submucosal dissection of gastric neoplasia.

BACKGROUND/AIMS: Vonoprazan is a new a potassium-competitive acid blocker (P-CAB) that was recently developed in Japan. However, vonoprazan's efficacy in healing gastric ulcers after endoscopic submucosal dissection (ESD) remains controversial. This study aimed to compare the efficacy of P-CABs and proton pump inhibitors (PPIs) in healing post-ESD ulcers. MATERIALS AND METHODS: This prospective randomized controlled trial (UMIN000017386) enrolled 40 patients with gastric neoplasia, who underwent ESD at our hospital from April 2015 to January 2016. Before ESD, patients were randomly divided into the following two groups: group V, vonoprazan 20 mg/day; or group R, rabeprazole 10 mg/day. Medications were taken 1 day before to 4 weeks after ESD. The ESD-induced artificial ulcer size was measured just after ESD and 4 weeks after ESD to calculate the reduction rate as follows: (ulcer area 4 weeks after ESD)/(ulcer area just after ESD) × 100. RESULTS: Eighteen patients in group V and 15 patients in group R were analyzed. The mean reduction rate was significantly different in groups V and R (93.3% vs 96.6%, respectively). Post-ESD bleeding was observed in two patients in group R and drug-induced hepatic injury in one patient in group R. CONCLUSION: Rabeprazole facilitated the healing process post-ESD.

The Chemical Chaperone 4-Phenylbutyric Acid Prevents Alcohol-Induced Liver Injury in Obese KK-Ay Mice.

BACKGROUND: Co-occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA)-which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress-on chronic-plus-binge ethanol (EtOH)-induced liver injury in a mouse model of obesity. METHODS: Male KK-Ay mice (8 weeks old) were fed a Lieber-DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair-fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage. RESULTS: Chronic-plus-binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic-plus-binge EtOH-induced up-regulation of ER stress-related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X-box-binding protein-1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic-plus-binge EtOH-induced expression of the oxidative stress marker heme oxygenase-1 (HO-1) and 4-hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO-1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH-induced hepatic activity of cytochrome P450 2E1. CONCLUSIONS: Binge EtOH intake after chronic consumption induces massive ER stress-related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic-plus-binge EtOH-induced liver injury by reducing ER and oxidative stress after an EtOH binge.

Cathepsin L-deficiency enhances liver regeneration after partial hepatectomy.

AIM: Cathepsin L (Ctsl) plays a pivotal role in lysosomal and autophagic proteolysis. Previous investigations revealed that partial hepatectomy (PH) decreases biosynthesis of cathepsins in liver, followed by suppression of lysosomal and autophagic proteolysis during liver regeneration. Conversely, it was reported that autophagy-deficiency suppressed liver regeneration. Thus, the purpose of this study is to determine if Ctsl deficiency affects liver regeneration after PH. METHODS: 70% of PH was performed in male Ctsl-deficient mice (Ctsl-/-) and wild-type littermates (Ctsl +/+) after PH. Mice were sacrificed and wet weight of the whole remaining liver was measured. Bromodeoxyuridine (BrdU)-immunostaining of liver sections was performed. Expression of cyclin D1, p62, LC-3, Nrf2, cleaved-Notch1, Hes1 was evaluated by western blot analysis. NQO1 mRNA expression was measured by realtime-PCR. RESULTS: After a 70% of PH, the liver mass was significantly restored within 5 days in Ctsl-/- mice compared to wild-type. Ctsl-deficiency enhanced the increases in both the rate of BrdU-positive cells and cyclin D1 expression after PH more than wild-type mice. On the other hand, Ctsl-deficiency upregulated p62, cleaved-Notch1 and Hes1 expression after PH. Moreover, the protein level of Nrf2 in the nucleus and mRNA expression of NQO1 in the liver after PH was also up-regulated in Ctsl-/- mice. CONCLUSIONS: These findings suggest that accumulation of p62 due to loss of Ctsl plays an important role in liver regeneration through activation of Nrf2-Notch1 signaling. Taken together, Ctsl might be a new therapeutic target on disorder of liver regeneration.

TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.

Successful remission of ulcerative colitis flare-up during pregnancy with adsorptive granulomonocytapheresis plus tacrolimus.

Ulcerative colitis (UC) is 1 of the 2 major phenotypes of chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms that impair function and quality of life. Further, IBD often affects women during childbearing age. Indeed, UC activity frequently increases during pregnancy, and the medications used to induce remission may adversely affect the health of the mother and the unborn child. We report successful induction of a remission in a UC case who experienced a flare-up in the first trimester of pregnancy. Upon relapse, she was treated with steroids and adsorptive granulomonocytapheresis (GMA) with the Adacolumn plus tacrolimus. This combination therapy induced a stable remission that was maintained during her entire pregnancy. She gave birth to a healthy child at 36 weeks of pregnancy with no maternal or fetal complications. Our experience indicates that GMA, as a non-drug therapeutic intervention with a favorable safety profile, plus tacrolimus might be a relevant treatment option for patients with active IBD during pregnancy. A future study of a large cohort of pregnant patients should strengthen our findings.

The Microbial Composition of Bacteroidetes Species in Ulcerative Colitis Is Effectively Improved by Combination Therapy With Fecal Microbiota Transplantation and Antibiotics.

Background: We previously reported that fresh fecal microbiota transplantation (FMT) after triple-antibiotic therapy (amoxicillin, fosfomycin, and metronidazole [AFM]; A-FMT) synergistically contributed to the recovery of phylum Bacteroidetes composition associated with the endoscopic severity and treatment efficacy of ulcerative colitis (UC). Here, we performed further microbial analyses using a higher-resolution method to identify the key bacterial species in UC and determine whether viable Bacteroidetes species from donor feces were successfully colonized by A-FMT. Methods: The taxonomic composition of Bacteroidetes in 25 healthy donors and 27 UC patients at baseline was compared at the species level using a heat-shock protein (hsp) 60-based microbiome method. Microbiota alterations before and after treatment of UC patients were also analyzed in 24 cases (n = 17 A-FMT; n = 3 mono-AFM; n = 4 mono-FMT). Results: We found species-level dysbiosis within the phylum Bacteroidetes in UC samples, which was associated with reduced species diversity, resulting from hyperproliferation and hypoproliferation of particular species. Moreover, in responders treated with A-FMT, diversity was significantly recovered at 4 weeks after a fresh round of FMT, after which high degrees of similarity in Bacteroidetes species composition among recipients and donors were observed. Conclusions: A-FMT alleviated intestinal dysbiosis, which is caused by the loss of Bacteroidetes species diversity in patients with UC. Eradication of dysbiotic indigenous Bacteroidetes species by AFM pretreatment might promote the colonization of viable Bacteroidetes cells, thereby improving the intestinal microbiota dysbiosis induced by UC. Our findings serve as a basis for further investigations into the mechanisms of FMT.

Effect of Esophageal Endoscopic Submucosal Dissection on Motility and Symptoms: A Prospective Study.

BACKGROUND: Endoscopic submucosal dissection (ESD) of esophageal tumors can cause stenosis, yet the effect of esophageal ESD on motility remains unclarified. This study aimed to compare esophageal motility and symptoms, before and after ESD, using high-resolution manometry (HRM) and symptom scoring. METHODS: Twenty-eight patients with 35 cT1a cancers were prospectively enrolled between December 2014 and February 2016. Pre- and post-ESD symptom score and HRM were recorded. Based on circumferential resection (CR), patients were divided into group A (n = 17, <2/3 CR) or B (n = 11, 2/3 CR or greater). HRM parameters evaluated were distal contractile integral (DCI), contractile front velocity (CFV), intrabolus pressure, integrated relaxation pressure, distal latency, and peristaltic breaks. RESULTS: Symptom scores worsened after ESD in 8/11 patients in group B, and 0/17 patients in group A. There was no significant difference in any HRM parameter after ESD in the whole study group but mean DCI tended to increase (p = 0.07). In group B, DCI increased significantly after ESD (p = 0.04), and CFV tended to decrease after ESD (p = 0.08). CONCLUSIONS: DCI tended to increase after esophageal ESD. ESD affected the symptom score and esophageal motility in cases with 2/3 CR or greater. This trial is registered with UMIN000015829.

Usefulness of Demarcation of Differentiated-Type Early Gastric Cancers after Helicobacter pylori Eradication by Magnifying Endoscopy with Narrow-Band Imaging.

BACKGROUND/AIMS: Early gastric cancer after Helicobacter pylori (Hp) eradication is difficult to demarcate. We used the vessel plus surface classification system (VSCS) to determine whether magnifying endoscopy with narrow-band imaging (ME-NBI) could demarcate differentiated-type early gastric cancers after Hp eradication, and to identify causes of an unclear demarcation line (DL). METHODS: Among 100 lesions of differentiated-type early gastric cancer resected endoscopically, 34 lesions in the Hp-eradicated group and 66 in the Hp-infected group were retrospectively compared. Clinicopathological factors and ME-NBI findings, including the presence or absence of the DL, were examined. Histopathologically, histological gastritis, the surface structure at the tumor border, well-differentiated adenocarcinoma with low-grade atypia (tub1-low), and non-neoplastic epithelium (NE) coverage rate on the tumor surface and at the tumor border were evaluated. RESULTS: DL (-) cases were more frequent in the Hp-eradicated group (11.8%, 4/34) than in the Hp-infected group (1.5%, 1/66; p < 0.05). The Hp-eradicated group had a higher NE coverage rate than the Hp-infected group (p < 0.05). All DL (-) cases had tub1-low or NE at the tumor border. CONCLUSION: ME-NBI with VSCS can identify the DL in most patients (88.2%) with differentiated-type early gastric cancer after Hp eradication.