Papers - Kanai, Takanori

Red dichromatic imaging reduces bleeding and hematoma during submucosal injection in esophageal endoscopic submucosal dissection

Miyazaki K., Kato M., Sasaki M., Iwata K., Masunaga T., Kubosawa Y., Hayashi Y., Mizutani M., Kiguchi Y., Takatori Y., Mutaguchi M., Matsuura N., Nakayama A., Takabayashi K., Kanai T., Yahagi N.

Surgical Endoscopy (Surgical Endoscopy)   2022

ISSN  09302794

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Background: Bleeding and hematoma formation during submucosal injection in esophageal endoscopic submucosal dissection (ESD) reduce the visibility of the submucosa. Red dichromatic imaging (RDI) is an endoscopic technique that provides better visualization of the deep submucosal blood vessels. We speculated that blood vessel injury could be avoided with RDI. This pilot study evaluated the role of RDI in preventing bleeding and hematoma formation during esophageal ESD. Methods: This was a single-center retrospective observational study. We examined 60 patients who underwent ESD with white light imaging (WLI) and RDI. A single endoscopist reviewed all of the surgical videos to document the incidence and severity of bleeding episodes. Eighteen videos provided adequate quality and detail, and the number of blood vessels traversing the mucosal incision lines of the lesions in these videos was evaluated under WLI and RDI. Results: The WLI group had a significantly higher incidence of hematomas per unit area compared to the RDI group (0.18/cm2 [range 0–0.38] vs. 0 [0–0.18]/cm2, p = 0.024). The WLI group also had a significantly higher incidence of total bleeding episodes compared to the RDI group (42.9% [range 21.7–60.4] vs 16.7% [range 13.8–22.9], p < 0.001). Significantly more blood vessels were visible under RDI compared to WLI (5 [range 4–8] vs. 2 [range 1–5], p = 0.0020). Conclusion: RDI reduced the incidence of bleeding and hematoma formation during submucosal injection in esophageal ESD. It was assumed that the improvement of blood vessel visibility by RDI might have contributed to the result.

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Feasibility and Safety of Endoscopic Ischemic Polypectomy and Clinical Outcomes in Patients with Peutz–Jeghers Syndrome (with Video)

Limpias Kamiya K.J.L., Hosoe N., Takabayashi K., Okuzawa A., Sakurai H., Hayashi Y., Miyanaga R., Sujino T., Ogata H., Kanai T.

Digestive Diseases and Sciences (Digestive Diseases and Sciences)   2022

ISSN  01632116

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Objectives: Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant hereditary disease with a clinical features related to gastrointestinal (GI) hamartomatous polyposis, frequently observed in the small bowel. Balloon-assisted enteroscopy (BAE) has made non-surgical treatment of GI polyps possible. Endoscopic mucosal resection (EMR) has been performed but was associated with complications and difficulties. Recently, endoscopic ischemic polypectomy (EIP) has been developed and its usefulness reported. The study evaluated the feasibility and safety of EIP and the clinical outcomes of patients with PJS. Methods: We retrospectively collected data of consecutive patients with PJS between September 2009 and March 2021. Data regarding clinical characteristics, follow-up methods, endoscopic management, and complications were collected. EIP feasibility and safety were assessed. Results: Twenty-two patients were included. The observation period was 70 months (range, 5–153). Of the 124 therapeutic endoscopy procedures performed, 68 used BAE. Of the 607 polyps treated, 329 polyps were located in the small bowel. EIP was able to treat a greater number of polyps per patient than EMR (P < 0.003), without any complications, carcinoma, or intussusception in the small bowel (P < 0.001). During the follow-up period, 3 patients developed GI cancer. Conclusion: Long-term follow-up in patients with PJS showed that EIP was a feasible and safe technique.

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Efficacy of capnographic and bispectral index monitoring on trans-oral therapeutic endoscopy: A prospective observational study

Hayashi Y., Hosoe N., Takabayashi K., Limpias Kamiya K.J.L., Tojo A., Sakurai H., Kinoshita S., Sujino T., Nakayama A., Kato M., Yahagi N., Ogata H., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) (Journal of Gastroenterology and Hepatology (Australia))   2022

ISSN  08159319

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Background and Aim: Oral therapeutic and invasive endoscopy requires deep sedation to reduce patient distress due to prolonged examination and procedures. The usefulness of capnography and bispectral index (BIS) monitoring in the early hypoxia detection in oral therapeutic and invasive endoscopy has yet to be evaluated. This study aimed to investigate the clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures. Methods: This is a prospective observational study. Trans-oral non-intubated therapeutic and/or invasive endoscopic procedures were performed with conventional monitoring (pulse oximetry, pulse, and blood pressure) as well as additional monitoring (BIS and end-tidal CO2 concentration). Hypoxia is defined as oxygen saturation of <90% that lasts >15 s. The clinical impact of capnography and BIS monitoring on hypoxic events during oral therapeutic and invasive endoscopic procedures were investigated with the risk factors for hypoxia in each patient. Results: Patients with hypoxia had significantly more apneas detected using capnography than other patients. The multivariate analysis revealed the detected apnea by capnography as an independent risk factor for hypoxia (odds ratio: 3.48[95% confidence interval: 1.24–9.78], P = 0.02). The BIS was not significantly different as a risk factor for hypoxia; however, per-event analysis revealed significantly decreased BIS values over time in 3 min before hypoxic events. Conclusions: Apnea detected by capnography was an independent predictor of hypoxia. The BIS value was not associated with hypoxia events; however, it showed a significant downward trend before hypoxia events.

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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature (Nature)  600 ( 7889 ) 472 - 477 2021.12

ISSN  00280836

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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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CD8⁺ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells

Koda Y., Teratani T., Chu P.S., Hagihara Y., Mikami Y., Harada Y., Tsujikawa H., Miyamoto K., Suzuki T., Taniki N., Sujino T., Sakamoto M., Kanai T., Nakamoto N.

Nature Communications (Nature Communications)  12 ( 1 )  2021.12

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Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103−CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

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Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Shiba S., Nakamoto N., Chu P.S., Ojiro K., Taniki N., Yamaguchi A., Morikawa R., Katayama T., Yoshida A., Aoki R., Teratani T., Suzuki T., Miyamoto T., Hara S., Yokoyama A., Kanai T.

Scientific Reports (Scientific Reports)  11 ( 1 )  2021.12

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Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.

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Clinical Characteristics of Patients with Coronavirus Disease (COVID-19): Preliminary Baseline Report of Japan COVID-19 Task Force, a Nationwide Consortium to Investigate Host Genetics of COVID-19

Tanaka H., Lee H., Morita A., Namkoong H., Chubachi S., Kabata H., Kamata H., Ishii M., Hasegawa N., Harada N., Ueda T., Ueda S., Ishiguro T., Arimura K., Saito F., Yoshiyama T., Nakano Y., Mutoh Y., Suzuki Y., Murakami K., Okada Y., Koike R., Kitagawa Y., Tokunaga K., Kimura A., Imoto S., Miyano S., Ogawa S., Kanai T., Fukunaga K.

International Journal of Infectious Diseases (International Journal of Infectious Diseases)  113   74 - 81 2021.12

ISSN  12019712

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Background and design:: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. Results:: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45–71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. Conclusions:: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

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Pathogenesis and management of gastrointestinal inflammation and fibrosis: from inflammatory bowel diseases to endoscopic surgery

Iwata K., Mikami Y., Kato M., Yahagi N., Kanai T.

Inflammation and Regeneration (Inflammation and Regeneration)  41 ( 1 )  2021.12

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Gastrointestinal fibrosis is a state of accumulated biological entropy caused by a dysregulated tissue repair response. Acute or chronic inflammation in the gastrointestinal tract, including inflammatory bowel disease, particularly Crohn’s disease, induces fibrosis and strictures, which often require surgical or endoscopic intervention. Recent technical advances in endoscopic surgical techniques raise the possibility of gastrointestinal stricture after an extended resection. Compared to recent progress in controlling inflammation, our understanding of the pathogenesis of gastrointestinal fibrosis is limited, which requires the development of prevention and treatment strategies. Here, we focus on gastrointestinal fibrosis in Crohn’s disease and post-endoscopic submucosal dissection (ESD) stricture, and we review the relevant literature.

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Esophageal endoscopic submucosal dissection on postendoscopic variceal ligation scars with injection under red dichromatic imaging

Miyazaki K., Kato M., Matsuura N., Kanai T., Yahagi N.

VideoGIE (VideoGIE)  6 ( 12 ) 536 - 539 2021.12

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Concordance analysis of microsatellite instability status between polymerase chain reaction based testing and next generation sequencing for solid tumors

Shimozaki K., Hayashi H., Tanishima S., Horie S., Chida A., Tsugaru K., Togasaki K., Kawasaki K., Aimono E., Hirata K., Nishihara H., Kanai T., Hamamoto Y.

Scientific Reports (Scientific Reports)  11 ( 1 )  2021.12

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Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, a polymerase chain reaction (PCR)-based method, was the first tumor-agnostic companion diagnostic to detect MSI status in MSI-H solid tumors. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available; however, its real-world concordance with PCR-based testing of MSI-H/dMMR remains to be investigated. The co-primary end points included the positive and negative predictive values of MSI-H/dMMR. A retrospective analysis of 80 patients who had undergone both MSI testing and NGS between July 2015 and March 2021 was conducted. Five patients were confirmed to have MSI-H in both examinations. Among the 75 patients diagnosed as microsatellite stable (MSS) by PCR-based testing, one with pancreatic cancer was diagnosed as having MSI-H after NGS. One patient with pancreatic cancer was diagnosed as having MSS in both tests was found to have a mutation in MLH1 by NGS, which was confirmed as dMMR by IHC staining. NGS had positive and negative predictive values of 100% (5/5) and 98.7% (74/75), respectively, for MSI-H. The concordance between NGS and PCR-based testing was 98.8% (79/80). Thus, NGS can be useful for evaluating MSI/MMR status in clinical practice and can be an important alternative method for detecting MSI-H/dMMR in the future.

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Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

Aoki R., Onuki M., Hattori K., Ito M., Yamada T., Kamikado K., Kim Y.G., Nakamoto N., Kimura I., Clarke J.M., Kanai T., Hase K.

Microbiome (Microbiome)  9 ( 1 )  2021.12

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Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion: These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. [MediaObject not available: see fulltext.]

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: Study protocol

Nakagawara K., Namkoong H., Terai H., Masaki K., Tanosaki T., Shimamoto K., Lee H., Tanaka H., Okamori S., Kabata H., Chubachi S., Ikemura S., Kamata H., Yasuda H., Kawada I., Ishii M., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Kagyo J., Shiomi T., Ohgino K., Sayama K., Otsuka K., Miyao N., Odani T., Oyamada Y., Masuzawa K., Nakayama S., Suzuki Y., Baba R., Nakachi I., Kuwahara N., Ishiguro T., Mashimo S., Minematsu N., Ueda S., Manabe T., Funatsu Y., Koh H., Yoshiyama T., Saito F., Ishioka K., Takahashi S., Nakamura M., Goto A., Harada N., Kusaka Y., Nakano Y., Nishio K., Tateno H., Edahiro R., Takeda Y., Kumanogoh A., Kodama N., Okamoto M., Umeda A., Hagimura K., Sato T., Miyazaki N., Takemura R., Sato Y., Takebayashi T., Nakahara J., Mimura M., Ogawa K., Shimmura S., Negishi K., Tsubota K., Amagai M., Goto R., Ibuka Y., Hasegawa N., Kitagawa Y., Kanai T., Fukunaga K.

BMJ Open Respiratory Research (BMJ Open Respiratory Research)  8 ( 1 )  2021.11

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Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

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Leucine-Rich Alpha-2 Glycoprotein May Be Predictive of the Adalimumab Trough Level and Antidrug Antibody Development for Patients with Inflammatory Bowel Disease: A Sub-Analysis of the PLANET Study

Yanai S., Shinzaki S., Matsuoka K., Mizuno S., Iijima H., Naka T., Kanai T., Matsumoto T.

Digestion (Digestion)  102 ( 6 ) 929 - 937 2021.11

ISSN  00122823

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Introduction: The aim of this study was to examine whether biomarkers are predictive of the adalimumab (ADA) trough level and antidrug antibody development in patients with Crohn's disease (CD) and ulcerative colitis (UC). Methods: Using data obtained in a prospective, multicenter, observational study (PLANET), we assessed serial changes in a novel biomarker-leucine-rich alpha-2 glycoprotein (LRG)-during ADA treatment for patients with active CD and UC. We measured serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCAL) at weeks 0, 12, 24, and 52. The ADA trough level and anti-ADA antibody (AAA) were also measured at weeks 12 and 52. Correlations between the ADA trough level, AAA, and biomarkers were examined. Results: In all, 34 patients with CD and 47 patients with UC were enrolled. The ADA trough level at week 12 or at the time of ADA withdrawal was 8.5 ± 3.9 in the AAA-negative group (n = 70) and 2.9 ± 2.7 μg/mL in the AAA-positive group (n = 8) (p < 0.0001). The ADA trough level at week 12 or at the time of ADA withdrawal was associated with pretreatment LRG (p = 0.0437 and r =-0.23). Conclusion: LRG, rather than CRP or fCAL, may be a marker for predicting the trough level of ADA for patients with CD and UC treated with ADA.

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Risk factors for prolonged hospital stay after endoscopy

Nishizawa T., Yoshida S., Toyoshima O., Matsuno T., Irokawa M., Arano T., Ebinuma H., Suzuki H., Kanai T., Koike K.

Clinical Endoscopy (Clinical Endoscopy)  54 ( 6 ) 851 - 856 2021.11

ISSN  22342400

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Background/Aims: The recovery room used after endoscopy has limited capacity, and an efficient flow of the endoscopy unit is desired. We investigated the duration of hospital stay after endoscopy and the risk factors for prolonged hospital stay among outpatients. Methods: We retrospectively studied consecutive patients who underwent esophagogastroduodenoscopy or colonoscopy at the Toyoshima Endoscopy Clinic. We collected data on age, sex, body weight, midazolam and pethidine dosage, respiratory depression during endoscopy, and duration of hospital stay after endoscopy (scope out to check out). Risk factors for prolonged hospital stay (>100 minutes) were identified using multiple logistic regression analysis. Results: We enrolled 3,898 patients, including 3,517 (90.2%) patients tested under sedation and 381 (9.8%) patients tested without sedation. Overall, 442 (11.3%) patients had prolonged stay (>100 min). The mean time difference between sedation group and non-sedation group was 44.2 minutes for esophagogastroduodenoscopy and 39.1 minutes for colonoscopy. Age (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.014−1.036), female sex (OR, 1.657; 95% CI, 1.220−2.249), and midazolam dose (OR, 1.019; 95% CI, 1.013−1.026) were independently associated with prolonged hospital stay after esophagogastroduodenoscopy, with similar results for colonoscopy. Conclusions: Old age, female sex, and midazolam dose were independent risk factors for prolonged hospital stay after endoscopy.

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アルコール関連肝疾患患者に対する内科医によるセリンクロ錠投与の飲酒量低減に対する効果

堀江 義則, 谷木 信仁, ちょ 柏松, 中本 伸宏, 金井 隆典

肝臓 ((一社)日本肝臓学会)  62 ( 10 ) 620 - 629 2021.10

ISSN  0451-4203

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アルコール関連肝疾患患者がアルコール依存症に至っている場合,簡易介入のみでは飲酒量の低減に結び付かないケースが多い.セリンクロ錠(一般名:ナルメフェン)は,飲酒欲求を抑え飲酒量を低減させる新しい薬剤である.今回,内科外来でセリンクロ錠を処方した症例を検討し,その有用性を検討した.初回投与から24週以上経過した症例は18例で,2例はめまいのため中止し,5例は連絡なく通院を中断したため,結果として副作用もなく通院を継続し24週での評価ができた症例は11例であった.全例で飲酒量の低減と肝機能の改善を認めたが,1例はその後再度飲酒量が増え,専門医療機関に紹介入院となった.セリンクロ錠による飲酒量低減が認められ,内科外来における飲酒量低減治療の新たな選択肢となることが示唆された.一方で,中断例も認められ,めまいや嘔吐などの副作用が多いことが報告されており,十分に研修を積んだ医師が処方すべきと考えられる.(著者抄録)

Linked color imaging versus white light imaging colonoscopy for colorectal adenoma detection: A randomized controlled trial

Miyaguchi K., Takabayashi K., Saito D., Tsuzuki Y., Hirooka N., Hosoe N., Ohgo H., Ashitani K., Soma H., Miyanaga R., Kimura K., Tokunaga S., Mitsui T., Miura M., Ozaki R., Nakamoto H., Kanai T., Hisamatsu T., Ogata H., Imaeda H.

Journal of Gastroenterology and Hepatology (Australia) (Journal of Gastroenterology and Hepatology (Australia))  36 ( 10 ) 2778 - 2784 2021.10

ISSN  08159319

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Background and Aim: The adenoma detection rate is an important indicator of colonoscopy quality and colorectal cancer incidence. We compared the adenoma detection rates between white light imaging (WLI) and linked color imaging (LCI) colonoscopy. Methods: Patients undergoing colonoscopy for positive fecal immunochemical tests, follow-up of colon polyps, and abdominal symptoms at three institutions were randomly assigned to the LCI or WLI groups. Mean adenoma number per patient (including based on endoscopists' experience), adenoma detection rate, cecal intubation time, withdrawal time, mean adenoma number per location, and adenoma size were compared. Results: The LCI and WLI groups comprised 494 and 501 patients, respectively. No significant differences in the cecal intubation rate (LCI vs WLI: 99.5% vs 99.4%), cecal intubation time, and withdrawal time were noted between groups. The mean adenoma number per patient was significantly higher in the LCI group than in the WLI group (1.07 vs 0.88, P = 0.04), particularly in the descending [0.12 (58/494) vs 0.07 (35/501), P = 0.01] and sigmoid colon [0.41 (201/494) vs 0.30 (149/501), P ≤ 0.001]. However, the adenoma detection rate was 47.1% in the LCI group and 46.9% in the WLI group, with no significant difference (P = 0.93). The total number of sessile-type adenomas was significantly higher in the LCI group than in the WLI group (346/494 vs 278/501, P = 0.04). As for polyp size, small polyps (≤ 5 mm) were detected at a significantly higher rate in the LCI group (271/494 vs 336/501, P = 0.04). Conclusion: Linked color imaging is significantly superior to WLI in terms of mean adenoma number per patient.

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Predictors of technical difficulty for complete closure of mucosal defects after duodenal endoscopic resection

Mizutani M., Kato M., Sasaki M., Masunaga T., Kubosawa Y., Hayashi Y., Kiguchi Y., Takatori Y., Mutaguchi M., Matsuura N., Nakayama A., Fukuhara S., Takabayashi K., Maehata T., Kanai T., Yahagi N.

Gastrointestinal Endoscopy (Gastrointestinal Endoscopy)  94 ( 4 ) 786 - 794 2021.10

ISSN  00165107

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Background and Aims: It has been reported that the prophylactic closure of mucosal defects after duodenal endoscopic resection (ER) can reduce delayed adverse events; however, under certain circumstances, this can be technically challenging. Therefore, the aim of this study was to determine the predictors of difficulty during the complete closure of mucosal defects after duodenal ER. Methods: This was a retrospective study of duodenal lesions that underwent ER between July 2010 and May 2020. We reviewed the endoscopic images and analyzed the relationships between the degree of closure or closure time and clinical features of the lesions using univariate and multivariate analyses. Results: We analyzed 698 lesions. The multivariate analysis revealed that lesion location in the medial or anterior wall (odds ratio, 2.8; 95% confidence interval, 1.36-5.85; P < .01) and a large lesion size (odds ratio, 1.4; 95% confidence interval, 1.07-1.89; P = .03) were independent predictors of an increased risk of incomplete closure. Moreover, a large lesion size (β coefficient, .304; P < .01), an occupied circumference over 50% (β coefficient, .178; P < .01), intraoperative perforation (β coefficient, .175; P < .01), treatment period (β coefficient, .143; P < .01), and treatment with endoscopic submucosal dissection (β coefficient, .125; P < .01) were independently and positively correlated with a prolonged closure time in the multiple regression analysis. Conclusions: This study revealed that lesion location in the medial or anterior wall and lesion size affected the incomplete closure of mucosal defects after duodenal ER, and lesion size, occupied circumference, intraoperative perforation, treatment period, and treatment method affected closure time.

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Hepatic Adenosine Triphosphate Reduction Through the Short-Chain Fatty Acids–Peroxisome Proliferator-Activated Receptor γ–Uncoupling Protein 2 Axis Alleviates Immune-Mediated Acute Hepatitis in Inulin-Supplemented Mice

Yamaguchi A., Teratani T., Chu P.s., Suzuki T., Taniki N., Mikami Y., Shiba S., Morikawa R., Amiya T., Aoki R., Kanai T., Nakamoto N.

Hepatology Communications (Hepatology Communications)  5 ( 9 ) 1555 - 1570 2021.09

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How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferon-γ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γ-type peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA–PPARγ–UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA–PPARγ–UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future.

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Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies

Kinouchi K., Mikami Y., Kanai T., Itoh H.

Molecular Aspects of Medicine (Molecular Aspects of Medicine)  80 2021.08

ISSN  00982997

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Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

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New strategy for evaluating pancreatic tissue specimens from endoscopic ultrasound-guided fine needle aspiration and surgery

Fukuhara S., Iwasaki E., Iwano T., Machida Y., Tamagawa H., Kawasaki S., Seino T., Yokose T., Endo Y., Yoshimura K., Kashiwagi K., Kitago M., Ogata H., Takeda S., Kanai T.

JGH Open (JGH Open)  5 ( 8 ) 953 - 958 2021.08

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Background and Aim: Preoperative histological evaluation of pancreatic neoplasms is important for guiding the resection strategy and preventing postoperative adverse events. However, conventional endoscopic methods have technical limitations that reduce the accuracy of the histopathological examination. Probe electrospray ionization mass spectrometry (PESI-MS) may be a useful technique for rapidly evaluating small specimens. Methods: This single-center prospective study included patients with pancreatic neoplasms between October 2018 and December 2019. Pancreatic ductal adenocarcinoma (PDAC) specimens were obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and non-neoplastic tissue was obtained via surgery. Specimens were subjected to PESI-MS and the mass spectra were analyzed using partial least squares regression-discriminant analysis. Results: The study included 40 patients with 20 nonneoplastic specimens and 19 PDAC specimens (1 case of neuroendocrine carcinoma was omitted). All nonneoplastic specimens were sufficient for PESI-MS analysis, although only 7 of 19 PDAC specimens were sufficient for PESI-MS analysis because of poor sample quality or insufficient quantity (<1 mg). Among the 27 analyzed cases, the mass spectra clearly differentiated between the PDAC and nonneoplastic specimens. Conclusions: This study revealed that PESI-MS could differentiate between PDAC and nonneoplastic specimens, even in cases where EUS-FNA produced very small specimens.

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