永山 学

BACKGROUND: Endoscopic balloon dilation (EBD) is an effective, minimally invasive treatment for Crohn's disease (CD) related intestinal strictures. However, restenosis frequently occurs and requires repetitive EBD or surgical resection. Since previous studies could not evaluate restenosis based on stricture diameter, factors affecting restenosis after EBD were unclear. This study aimed to identify these factors by precisely measuring the diameter of small intestinal strictures in patients with CD. METHODS: This single-center retrospective study enrolled patients with CD with de novo small intestinal strictures who underwent two double-balloon enteroscopy sessions (EBD and follow-up) between January 2016 and October 2021. Clinical and endoscopic data were obtained from electronic medical records. A calibrated small-caliber-tip transparent hood was used to precisely measure stricture diameters. Multivariate analysis was performed to identify factors associated with restenosis. RESULTS: Forty-eight patients (37 male) were analyzed. The total number of strictures detected decreased from 162 to 143. The mean diameter of all strictures and the narrowest stricture in each patient increased significantly from 8.6 to 9.8 mm and from 7.6 to 8.7 mm, respectively. Thirty-two (67%) patients developed endoscopic restenosis. Multivariate analysis showed that the presence of ulcers at the follow-up session was a risk factor for restenosis (odds ratio 9.4, p = 0.01). Patients with complete mucosal healing at both sessions (n = 21) showed significant improvement in the narrowest stricture (+1.7 mm, p = 0.001). CONCLUSIONS: Maintenance of complete mucosal healing is significantly associated with avoiding restenosis after EBD in CD-related small intestinal strictures.

The pink color sign in iodine unstained areas is useful to differentiate esophageal squamous cell carcinoma (ESCC) from other lesions. However, some ESCCs have obscure color findings which affect the ability of endoscopists to differentiate these lesions and determine the resection line. Using white light imaging (WLI), linked color imaging (LCI) and blue laser imaging (BLI), 40 early ESCCs were retrospectively evaluated using images before and after iodine staining. Visibility scores for ESCC by expert and non-expert endoscopists were compared using these three modalities and color differences measured for malignant lesions and surrounding mucosa. BLI had the highest score and color difference without iodine staining. Each determination with iodine was much higher than without iodine regardless of the modality. With iodine, ESCC mainly appeared pink, purple and green using WLI, LCI and BLI, respectively and visibility scores determined by non-experts and experts were significantly higher for LCI (both p < 0.001) and BLI (p = 0.018 and p < 0.001) than for WLI. The score with LCI was significantly higher than with BLI among non-experts (p = 0.035). With iodine, the color difference using LCI was twice that with WLI and one with BLI was significantly larger than with WLI (p < 0.001). These greater tendencies were found regardless of location, depth of cancer or intensity of pink color using WLI. In conclusion, areas of ESCC unstained by iodine were easily recognized using LCI and BLI. Visibility of these lesions is excellent even by non-expert endoscopists, suggesting that this method is useful to diagnose ESCC and determine the resection line.

Nonalcoholic fatty liver disease (NAFLD), a hepatic characteristic of metabolic syndrome, received significant attention in clinical settings. The multiple-hit theory is one of the proposed mechanisms of NAFLD, and gut dysbiosis is considered a hit. Thus, controlling gut microbiota is a potential target in the management of NAFLD, and probiotics can be used as a treatment agent for NAFLD. The current study aimed to investigate the efficacy of probiotics against nonalcoholic steatohepatitis in a hepatocyte-specific PTEN knockout mouse model that mimics the characteristics of human NAFLD. Probiotics were administered to male knockout mice for 8 or 40 weeks. Next, we assessed hepatic inflammation, fibrosis, carcinogenesis, and oxidative stress. Probiotics were found to reduce serum transaminase levels, NAFLD activity score, and the gene expression of pro-inflammatory cytokines. In addition, they decreased liver fibrosis grade, which was examined via Sirius red staining, gene expression of fibrotic markers, and hydroxyproline. Furthermore, probiotics suppressed the number of liver tumors, particular in HCC. Probiotics reduced oxidative stresses, including glutathione levels, and anti-oxidative stress marker, which may be an underlying mechanism for their beneficial effects. In conclusion, probiotics treatment had beneficial effects against NAFLD and carcinogenesis in hepatocyte-specific PTEN knockout mice.

Background and study aims  Ultrathin endoscopy causes a minimal gag reflex and has minimal effects on cardiopulmonary function. Linked color imaging (LCI) is useful for detection of malignancies in the digestive tract. The aim of this study was to clarify whether LCI with ultrathin endoscopy facilitates detection of early gastric cancer (EGC) despite its lower resolution compared with high-resolution white light imaging (WLI) with standard endoscopy. Patients and methods  This was a retrospective analysis with prospectively collected video, including consecutive 166 cases of EGC or gastric atrophy alone. Ninety seconds of screening video was collected using standard and ultrathin endoscopes with both WLI and LCI for each case. Three expert endoscopists assessed each video and the sensitivity of detecting EGC calculated. Color difference calculations were performed. Results  Sensitivities using ultrathin WLI, ultrathin LCI, standard WLI, and standard LCI for the identification of cancer were 66.0 %, 80.3 %, 69.9 %, and 84.0 %, respectively. The color difference between malignant lesions and surrounding mucosa with ultrathin LCI and standard LCI were significantly higher than using ultrathin WLI or standard WLI, supported subjectively by the visibility score. Ultrathin LCI color difference and visibility score were significantly higher than standard WLI. Conclusions  LCI with a low-resolution ultrathin endoscope is superior to WLI with a high-resolution standard endoscope for gastric cancer screening. This suggests that the high color contrast between EGC and the surrounding mucosa is more important than high-resolution images.

OBJECTIVES: Early gastric cancers (EGCs) of the elevated type or with submucosal invasion are easily found by routine endoscopy. However, most early cancers are challenging to detect because of subtle morphological or color differences from surrounding atrophic mucosa and intestinal metaplasia. Linked color imaging (LCI) enhances mucosal color difference, making it easier to detect EGCs. The aim of this study is to clarify the advantages and possible disadvantages of LCI for screening for obscure EGC. METHODS: A total of 665 malignant gastric lesions resected using endoscopic submucosal dissection between January 2015 and April 2018 were retrospectively reviewed. Obviously detectable lesions were not included in the main analysis when determining the target lesion. White light imaging (WLI)/LCI images of 508 endoscopically obscure malignant lesions were included in the final analysis and evaluated by three non-expert and three expert endoscopists using visibility scores for detection and extent. RESULTS: The detection visibility scores using LCI were significantly higher than those using WLI regardless of lesion characteristics including location, size, histological type, depth of invasion, and Helicobacter pylori status. The detection score improved in 46.4% cases and deteriorated in 4.9% when the modality changed from WLI to LCI. A mixed-effects multivariate logistic regression analysis showed that use of LCI (odds ratio [OR] 2.57), elevated type (OR 1.92), invasion to submucosa (OR 2.18) were significantly associated with improved visibility of EGC. CONCLUSIONS: Linked color imaging significantly improves visibility of EGC regardless of differences in lesion morphology, histology, location, depth of invasion, and H. pylori status compared to conventional WLI.

BACKGROUND : Many patients with familial adenomatous polyposis (FAP) have adenomatous polyps of the duodenum and the jejunum. We aimed to elucidate the long-term outcomes after double-balloon endoscopy (DBE)-assisted endoscopic resection of duodenal and jejunal polyps in patients with FAP. METHODS : We retrospectively reviewed patients who underwent more than two sessions of endoscopic resection using DBE from August 2004 to July 2018. RESULTS : A total of 72 DBEs were performed in eight patients (median age 30 years, range 12-53; 1.4 DBE procedures/patient-year) during the study period, and 1237 polyps were resected. The median observation period was 77.5 months (range 8-167). There were 11 adverse events, including seven delayed bleeds and four episodes of acute pancreatitis. No delayed bleeding occurred after cold polypectomy. Although, in one patient, one endoscopically resected duodenal polyp was diagnosed as being intramucosal carcinoma, none of the patients developed an advanced duodenal or jejunal cancer during the study period. CONCLUSIONS : Endoscopic resection of duodenal and jejunal polyposis using DBE in patients with FAP can be performed safely, efficiently, and effectively.

慢性炎症性腸疾患の一つであるクローン病は主に小腸と大腸を侵す疾患であり、大腸内視鏡で到達困難な小腸にも病変が多い。バルーン小腸内視鏡は診断のみならず、狭窄に対する内視鏡的バルーン拡張術(endoscopic balloon dilation;EBD)を施行することができ、これにより外科的切除を回避もしくは遅らせることができる。CASThood(calibrated small-caliber-tip transparent hood)は腸管狭窄に対して開発されたバルーン内視鏡用フードで、狭窄内径の正確な測定が可能で、先端細径によるブジー効果や高い挿入効率が期待でき、効率的なEBDを可能にする。多数の小腸狭窄が存在する場合には連続的に多くの狭窄をEBDする必要があり、そのためには適切なデバイスとストラテジーを用いる必要がある。日本を含む東アジア諸国ではクローン病の症例は増加しており、小腸内視鏡の必要性はさらに高まると思われる。(著者抄録)

Dysbiotic microbiota contributes to the pathogenesis of Crohn's disease (CD) by regulating the immune system. Although pro-inflammatory microbes are probably enriched in the small intestinal (SI) mucosa, most studies have focused on fecal microbiota. This study aimed to examine jejunal and ileal mucosal specimens from patients with CD via double-balloon enteroscopy. Comparative microbiome analysis revealed that the microbiota composition of CD SI mucosa differs from that of non-CD controls, with an increased population of several families, including Enterobacteriaceae, Ruminococcaceae, and Bacteroidaceae. Upon anaerobic culturing of the CD SI mucosa, 80 bacterial strains were isolated, from which 9 strains representing 9 distinct species (Escherichia coli, Ruminococcus gnavus, Klebsiella pneumoniae, Erysipelatoclostridium ramosum, Bacteroides dorei, B. fragilis, B. uniformis, Parabacteroides distasonis, and Streptococcus pasteurianus) were selected on the basis of their significant association with CD. The colonization of germ-free (GF) mice with the 9 strains enhanced the accumulation of TH1 cells and, to a lesser extent, TH17 cells in the intestine, among which an E. coli strain displayed high potential to induce TH1 cells and intestinal inflammation in a strain-specific manner. The present results indicate that the CD SI mucosa harbors unique pro-inflammatory microbiota, including TH1 cell-inducing E. coli, which could be a potential therapeutic target.

＜文献概要＞キャストフードは,狭窄の内径を計測可能とする目盛りが側面に刻まれた先端細径フードである.これを使用することで,無送気でも視野確保が容易で,適切なサイズの拡張用バルーンを選択でき,ガイドワイヤの挿入も容易となり,バルーン拡張後のスコープ通過も容易となる.無送気での腸間膜付着側の病変観察も,透明なフード側面を透して容易に可能であり,有用である.

＜文献概要＞キャストフードは,狭窄の内径を計測可能とする目盛りが側面に刻まれた先端細径フードである.これを使用することで,無送気でも視野確保が容易で,適切なサイズの拡張用バルーンを選択でき,ガイドワイヤの挿入も容易となり,バルーン拡張後のスコープ通過も容易となる.無送気での腸間膜付着側の病変観察も,透明なフード側面を透して容易に可能であり,有用である.

Commensal bacteria influence host physiology, without invading host tissues. We show that proteins from segmented filamentous bacteria (SFB) are transferred into intestinal epithelial cells (IECs) through adhesion-directed endocytosis that is distinct from the clathrin-dependent endocytosis of invasive pathogens. This process transfers microbial cell wall-associated proteins, including an antigen that stimulates mucosal T helper 17 (TH17) cell differentiation, into the cytosol of IECs in a cell division control protein 42 homolog (CDC42)-dependent manner. Removal of CDC42 activity in vivo led to disruption of endocytosis induced by SFB and decreased epithelial antigen acquisition, with consequent loss of mucosal TH17 cells. Our findings demonstrate direct communication between a resident gut microbe and the host and show that under physiological conditions, IECs acquire antigens from commensal bacteria for generation of T cell responses to the resident microbiota.

Strictures of the small intestine are a significant complication in patients with Crohn’s disease. Their treatment remains a major challenge. Surgical resection cannot cure Crohn’s disease. Multiple resection of strictures may lead to short bowel syndrome. The development of balloon-assisted enteroscopy has enabled balloon dilation for strictures in the deep small bowel. Because balloon dilation can be repeatedly performed for recurrence of strictures, it may avoid or postpone the need for surgery. In this article, we introduce strategies and devices for endoscopic balloon dilation therapy for Crohn’s disease strictures.

Background and Aims: It is difficult to secure the visual field during endoscopy for GI bleeding or colonoscopy without preparation because the injected water is rapidly mixed with fresh blood or stool. We developed a novel method to secure the visual field in these situations. Methods: Clear gel with the appropriate viscosity to prevent rapid mixing is injected through the accessory channel, instead of water. A vinyl tube was used as an in vitro GI bleeding model. After filling the lumen with indigo carmine dye, air insufflation and water injection are not effective for securing the visual field. However, after gel injection, the bleeding source is observed clearly in the space occupied by the gel. The efficacy of this method was evaluated subjectively in clinical use. From February 2014 until June 2015, gel immersion was used in 17 consecutive patients when the visual field could not be secured with routine insufflation. Results: Of these 17 patients, gel injection was very effective in 10, effective in 5, slightly effective in 1, and not effective in 1. There were no adverse events associated with this method. Conclusion: Gel immersion endoscopy is safe and effective for securing the visual field, creating a space for endoscopic visualization and treatment in otherwise difficult situations.

Background:Crohn's disease (CD) strictures of the small intestine are a feared complication and difficult to treat because of difficulty gaining access to the stricture site. The development of double-balloon endoscopy (DBE) enabled access to the entire small intestine with interventional capabilities. The aim of this study was to assess the long-term outcomes in patients with small intestinal strictures secondary to CD after DBE-assisted endoscopic balloon dilation (EBD).Methods:In this retrospective cohort study, DBE-assisted EBD was performed in 85 consecutive patients with CD strictures of the small intestine from 2002 to 2014. Follow-up data were available for 85 patients for a mean of 41.9 months (range, 0-141), and clinical outcomes were assessed.Results:Overall, 321 DBE-assisted EBD sessions (473 procedures) were performed in 85 patients during the study period. Most CD strictures were de novo (97%). The surgery-free rate after initial DBE-assisted EBD was 87.3% at 1 year and 78.1% at 3 years. The presence of a fistula was significantly associated with the need for surgical intervention (hazard ratio = 5.50, 95% confidence interval: 2.16-14.0, P &lt; 0.01). The surgery-free interval in patients with a fistula was significantly shorter than in patients without a fistula (P &lt; 0.01, log-rank test).Conclusions:DBE-assisted EBD provides a favorable long-term outcome in patients with small intestinal CD-associated strictures. DBE-assisted EBD for CD strictures is a safe and effective treatment to avoid or postpone surgery over the long-term.