Publications by authors named "Hiroshi Nakase"

288 Publications

Comparison of culture media for human intestinal organoids from the viewpoint of pharmacokinetic studies.

Biochem Biophys Res Commun 2021 Jun 10;566:115-122. Epub 2021 Jun 10.

Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan; Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, 565-0871, Japan. Electronic address:

Human intestinal organoids are expected to be applied in pharmaceutical research. Various culture media for human intestinal organoids have been developed, but it remains unclear which media are preferable for pharmacokinetic studies. Here, we cultured human intestinal organoids with three major culture media that are already used widely around the world: the medium of Sato et al. (S-medium; reported in 2011), Fujii et al. (F-medium; 2018), and Miyoshi et al. (M-medium; 2013). The growth of human intestinal organoids cultured in S-medium was faster than that in F- or M-medium. The gene expression levels of most pharmacokinetic-related enzymes or transporters in human intestinal organoids cultured in M-medium were higher than those in S- or F-medium, and comparable to those in the adult human small intestine. The level of cytochrome P450 (CYP) 3A4 activity was also highest in human intestinal organoids cultured in M-medium. Collectively, the results underscored the importance of selection and optimization of culture medium for various applications using human intestinal organoids, including pharmacokinetic studies.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.007DOI Listing
June 2021

[A case of mediastinal pancreatic pseudocyst diagnosed and treated successfully by endoscopic procedure].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(6):578-585

Department of Gastroenterology and Hepatology, Sapporo Medical University.

A 60-year-old man was admitted for investigation of a mediastinal cystic lesion. During endoscopic retrograde pancreatography, the contrast medium leaked from the head of the main pancreatic duct, and the cystic fluid collected with endoscopic ultrasonography (EUS) -guided aspiration showed high levels of pancreatic enzymes. Therefore, we diagnosed mediastinal pancreatic pseudocyst. The pseudocyst shrank as a result of EUS-guided drainage, and an endoscopic nasopancreatic drainage tube was then placed to close the fistula of the pancreatic duct. This case suggests that endoscopic procedures could be useful for the diagnosis and treatment of mediastinal pancreatic pseudocyst. We review 48 case reports of mediastinal pancreatic pseudocyst and discuss the usefulness of endoscopic procedures for diagnosis and treatment.
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http://dx.doi.org/10.11405/nisshoshi.118.578DOI Listing
June 2021

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

Anticancer Res 2021 Jun;41(6):2817-2828

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan;

Background/aim: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells.

Materials And Methods: To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed.

Results: Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients.

Conclusion: Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.
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http://dx.doi.org/10.21873/anticanres.15062DOI Listing
June 2021

Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment.

Intern Med 2021 May 22. Epub 2021 May 22.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.
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http://dx.doi.org/10.2169/internalmedicine.7098-21DOI Listing
May 2021

Autoimmune gastritis concomitant with gastric adenoma and subacute combined degeneration of the spinal cord.

BMJ Case Rep 2021 May 11;14(5). Epub 2021 May 11.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

A 62-year-old woman was referred to our department for further investigation of anaemia. Blood test showed macrocytic anaemia. Oesophagogastroduodenoscopy (OGD) revealed proximal-predominant gastric atrophy and flat elevated lesion in the gastric body. Several days after OGD, she complained of gait disturbance and was diagnosed with subacute combined degeneration of the spinal cord. Furthermore, laboratory tests showed positive for both anti-parietal cell and anti-intrinsic factor antibodies, as well as increased serum gastrin level and decreased pepsinogen I level, which confirmed the diagnosis of autoimmune gastritis (AIG). Anaemia and neurological symptoms were improved after vitamin B supplementation. Subsequently, the patient underwent gastric endoscopic submucosal dissection; histopathological examination revealed gastric adenoma. AIG can cause gastric neoplasms and vitamin B deficiency, with the latter resulting in pernicious anaemia and neurological disorders. These diseases are treatable but potentially life-threatening. This case highlights the importance of early diagnosis of AIG and proper management of its comorbidities.
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http://dx.doi.org/10.1136/bcr-2021-242836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118001PMC
May 2021

Gastrointestinal involvement in a patient with familial Mediterranean fever mimicking Crohn's disease: a case report.

Clin J Gastroenterol 2021 May 11. Epub 2021 May 11.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn's disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis; however, these findings, including the histopathology, did not confirm Crohn's disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1β monoclonal antibody (canakinumab). The patient's symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn's disease.
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http://dx.doi.org/10.1007/s12328-021-01426-2DOI Listing
May 2021

Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): a multicentre, open-label, randomised controlled trial.

Lancet Gastroenterol Hepatol 2021 06 20;6(6):429-437. Epub 2021 Apr 20.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan. Electronic address:

Background: Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab.

Methods: We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092.

Findings: Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1-90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0-69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7-44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0-44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI -10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9-90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.

Interpretation: Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account.

Funding: Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan.

Translation: For the Japanese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2468-1253(21)00062-5DOI Listing
June 2021

Evidence-based clinical practice guidelines for inflammatory bowel disease 2020.

J Gastroenterol 2021 Jun 22;56(6):489-526. Epub 2021 Apr 22.

Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.

Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.
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http://dx.doi.org/10.1007/s00535-021-01784-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137635PMC
June 2021

Successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19.

Clin J Gastroenterol 2021 Apr 11. Epub 2021 Apr 11.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 063-8543, Japan.

The coronavirus disease-2019 (COVID-19) has rapidly become a pandemic, resulting in a global suspension of non-emergency medical procedures such as screening endoscopic examinations. There have been several reports of COVID-19 patients presenting with gastrointestinal symptoms such as diarrhea and vomiting. In this report, we present a case of successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19. The case was under mechanical ventilation with extracorporeal membrane oxygenation (ECMO), and the airway was on a closed circuit. This indicates that COVID-19 is associated with not only lung injury but also intestinal damage, and that proper protective protocols are essential in guaranteeing the best outcomes for patients and clinical professionals during this pandemic.
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http://dx.doi.org/10.1007/s12328-021-01402-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038534PMC
April 2021

The characteristics of gastrointestinal symptoms in patients with severe COVID-19: a systematic review and meta-analysis.

J Gastroenterol 2021 05 23;56(5):409-420. Epub 2021 Mar 23.

Department of Gastroenterology and Hepatology, Sapporo Medical University of Medicine, S-1, W16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan.

Although primarily a respiratory illness, several studies have shown that COVID-19 causes elevation of liver enzymes and various gastrointestinal (GI) symptoms. The aim of this study was to undertake a systematic review and meta-analysis to determine whether the presence of gastrointestinal (GI) symptoms contributed toward COVID-19 severity, and identify the GI symptoms characteristic of severe COVID-19. We conducted a literature search of PubMed from December 1, 2019, to June 30, 2020, and identified all reports with GI symptoms reported. A meta-analysis comparing the severity of COVID-19 with the presence of liver enzyme elevation and GI symptoms was performed using RevMan version 5.4. Pooled data from 15,305 unique reverse transcriptase-polymerase chain reaction positive COVID-19 patients from 44 studies were analyzed. We found that the severe COVID-19 patients significantly had abdominal pain compared to the non-severe COVID-19 patients (OR = 2.70, 95% CI 1.17-6.27, Z = 2.32, p = 0.02, I = 0%) by analyzed 609 patients of 4 studies who reported both abdominal pain and COVID-19 severity. However, there was no significant difference in the incidence of diarrhea, nausea, or vomiting between the two groups. Thus, this systematic review and meta-analysis demonstrated that abdominal pain could be characteristic of severe COVID-19 infections. Compared with other viral infections that primarily infect the respiratory system, patients with COVID-19 have a slightly lower frequency of diarrheal symptoms with abdominal pain. However, to confirm this, further studies with COVID-19 patients across various countries and ethnicities are required.
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http://dx.doi.org/10.1007/s00535-021-01778-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987120PMC
May 2021

Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands.

Intern Med 2021 Mar 22. Epub 2021 Mar 22.

Department of Gastroenterology and Hepatology, Sapporo Medical University, Japan.

Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.
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http://dx.doi.org/10.2169/internalmedicine.6603-20DOI Listing
March 2021

Lower gastrointestinal bleeding from Dieulafoy's lesion in the transverse colon.

Dig Endosc 2021 May 27;33(4):e56-e57. Epub 2021 Feb 27.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan.

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http://dx.doi.org/10.1111/den.13936DOI Listing
May 2021

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan.

Background: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD.

Methods: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance.

Results: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%).

Conclusions: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.
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http://dx.doi.org/10.1093/ibd/izab004DOI Listing
January 2021

Idiopathic retroperitoneal fibrosis diagnosed by endoscopic ultrasonography-guided fine-needle biopsy.

JGH Open 2021 Jan 14;5(1):151-152. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology Sapporo Medical University School of Medicine Sapporo Japan.

We demonstrate a case, in which endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) was useful for determining the diagnosis of lesions of retroperitoneal fibrosis. In our case, accessing the retroperitoneal lesions by conventional percutaneous biopsy procedures was not feasible due to the difficulty of avoiding the inferior vena cava and ureter. We believe that our case demonstrates a unique approach for performing histological analysis in a challenging case.
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http://dx.doi.org/10.1002/jgh3.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812448PMC
January 2021

Concomitant use of an immunomodulator with ustekinumab as an induction therapy for Crohn's disease: A systematic review and meta-analysis.

J Gastroenterol Hepatol 2021 Jan 15. Epub 2021 Jan 15.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aim: Ustekinumab (UST), a fully humanized monoclonal antibody against the p40 subunit of interleukin-12/23, is effective for the treatment of Crohn's disease (CD). The benefit of concomitant use of an immunomodulator (IM) with UST, however, is unclear. This study aimed to provide a systematic review and meta-analysis comparing the efficacy and safety of concomitant use of an IM with UST as an induction therapy for CD patients.

Methods: A systematic literature search was performed using PubMed/MEDLINE, the Cochrane Library, and the Japana Centra Revuo Medicina from inception to October 31, 2019. The main outcome measure was achievement of clinical efficacy (remission, response, and clinical benefit) at 6-12 weeks. The quality of the included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tools. The fixed-effects model was used to calculate the pooled odds ratios.

Results: From 189 yielded articles, six including a total of 1507 patients were considered in this meta-analysis. Concomitant use of an IM with UST was significantly effective than UST monotherapy as an induction therapy (pooled odds ratio in the fixed-effects model: 1.35, 95% confidence interval [1.06-1.71], P = 0.015). The heterogeneity among studies was low (I  = 2.6%). No statistical comparisons of the occurrence of adverse events between UST monotherapy and concomitant use of an IM with UST were performed.

Conclusion: The efficacy of concomitant use of an IM with UST as an induction therapy for CD was significantly superior to that of monotherapy with UST.
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http://dx.doi.org/10.1111/jgh.15401DOI Listing
January 2021

Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.

Cell Death Discov 2021 Jan 12;7(1). Epub 2021 Jan 12.

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
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http://dx.doi.org/10.1038/s41420-020-00400-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803977PMC
January 2021

In Vivo Gene Expression Profile of Human Intestinal Epithelial Cells: From the Viewpoint of Drug Metabolism and Pharmacokinetics.

Drug Metab Dispos 2021 Mar 31;49(3):221-232. Epub 2020 Dec 31.

Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan

Orally administered drugs are absorbed and metabolized in the intestine. To accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of the genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from patients with cancer. In this study, to obtain more accurate gene expression profiles, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression analysis of drug-metabolizing enzymes (cytochromes P450), non-cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the cytochromes P450 expressed in the ileum were 25% (), 19% (), and 14% (). and were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as , peptide transporter 1, breast cancer resistance protein, , and were strongly expressed, and the expression levels of and in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as , , and were strongly expressed. We succeeded in obtaining gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs. SIGNIFICANCE STATEMENT: To obtain gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression profiles of drug-metabolizing enzymes (cytochromes P450), non-cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters in biopsy samples from the duodenum, ileum, colon, and rectum were obtained in this study.
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http://dx.doi.org/10.1124/dmd.120.000283DOI Listing
March 2021

A unique cause of chronic abdominal pain.

JGH Open 2020 Dec 16;4(6):1236-1237. Epub 2020 Sep 16.

Department of Gastroenterology and Hepatology Sapporo Medical University School of Medicine Sapporo Japan.

The images presented here demonstrated how we arrived at the diagnosis of infection in a 54-year-old man with chronic abdominal pain by capsule endoscopy (CE). In this case, computed tomography (CT) images were not representative, and further investigation with CE was required to confirm the diagnosis. The combination of CT and CE was useful for diagnosing Ascaris lumbricoides infection in this patient.
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http://dx.doi.org/10.1002/jgh3.12419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731804PMC
December 2020

Successful treatment with endoscopic transpapillary drainage for gallbladder perforation associated with steroid treatment for interstitial pneumonia (with video).

JGH Open 2020 Dec 30;4(6):1233-1235. Epub 2020 Jul 30.

Department of Gastroenterology and Hepatology Sapporo Medical University School of Medicine Sapporo Japan.

This case report highlights the clinical efficacy of endoscopic transpapillary drainage for gallbladder perforation in a high-risk surgical patient with a history of steroid treatment for interstitial pneumonia. The usefulness of endoscopic transpapillary gallbladder drainage in high-risk surgical patients with acute cholecystitis has not been established. In difficult cases of emergent surgery, such as described here, endoscopic transpapillary drainage is a promising method to manage gallbladder perforation and acute cholecystitis recurrence.
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http://dx.doi.org/10.1002/jgh3.12397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731810PMC
December 2020

Autophagy and Autophagy-Related Diseases: A Review.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Autophagy refers to the process involving the decomposition of intracellular components via lysosomes. Autophagy plays an important role in maintaining and regulating cell homeostasis by degrading intracellular components and providing degradation products to cells. In vivo, autophagy has been shown to be involved in the starvation response, intracellular quality control, early development, and cell differentiation. Recent studies have revealed that autophagy dysfunction is implicated in neurodegenerative diseases and tumorigenesis. In addition to the discovery of certain disease-causing autophagy-related mutations and elucidation of the pathogenesis of conditions resulting from the abnormal degradation of selective autophagy substrates, the activation of autophagy is essential for prolonging life and suppressing aging. This article provides a comprehensive review of the role of autophagy in health, physiological function, and autophagy-related disease.
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http://dx.doi.org/10.3390/ijms21238974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729615PMC
November 2020

Haemorrhagic exfoliative oesophagitis associated with nasogastric tube placement.

BMJ Case Rep 2020 Nov 23;13(11). Epub 2020 Nov 23.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan

A 92-year-old man hospitalised for cerebral infarction developed haematemesis. The patient was taking low-dose aspirin and apixaban for his cerebral infarction and non-valvular atrial fibrillation. His enteral nutrition was administrated through nasogastric tube. Upper endoscopy revealed active bleeding from a protruded lesion in the upper oesophagus. The lesion was removed by washing with a water jet, followed by successful endoscopic haemostasis. Histopathological examination revealed degenerated squamous epithelium without specific findings; the diagnosis was exfoliative oesophagitis. In our case, mechanical mucosal injury caused by nasogastric tube placement may result in exfoliative oesophagitis. In addition, the use of low-dose aspirin with apixaban may have contributed to the bleeding. We then performed a wire-guided nasogastric tube placement under fluoroscopy. No further bleeding was observed, but the patient died of sepsis 1 month later. This case highlights the importance of a risk assessment and management of oesophageal complications associated with nasogastric tube placement.
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http://dx.doi.org/10.1136/bcr-2020-237485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684668PMC
November 2020

Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.

The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.
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http://dx.doi.org/10.3390/ijms21218145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662299PMC
October 2020

Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial.

J Gastroenterol 2021 Feb 2;56(2):147-157. Epub 2020 Nov 2.

Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Miyazaki, Miyazaki, 889-1692, Japan.

Background: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC.

Methods: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0.

Results: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM.

Conclusions: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM.

Clinical Trial Registry: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .
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http://dx.doi.org/10.1007/s00535-020-01741-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862507PMC
February 2021

Does anti-tumor necrosis factor alpha prevent the recurrence of Crohn's disease? Systematic review and meta-analysis.

J Gastroenterol Hepatol 2021 Apr 14;36(4):864-872. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aim: Anti-tumor necrosis factor (TNF) α agents are now well known to function as effective treatments for Crohn's disease (CD). Several meta-analyses have revealed the efficacy of anti-TNF therapy for preventing recurrence after surgery; however, the efficacies reported in some prospective studies differed according to the outcomes. Moreover, adverse events (AEs) were not well evaluated. We conducted this systematic review and meta-analysis to evaluate both the efficacy of anti-TNF therapy after stratification by the outcome of interest and the AEs.

Methods: We performed a systematic literature review of studies investigating anti-TNF therapy, CD, and postoperative recurrence. Meta-analyses were performed for endoscopic and clinical recurrence and AEs.

Results: A total of 570 participants, including 254 patients in the intervention group and 316 patients in the control group, in eight studies, were analyzed for recurrence. Based on the results of the meta-analysis, the efficacies of anti-TNF therapy at preventing endoscopic and clinical recurrence were as follows: relative risk (RR) 0.34, 95% confidence interval (CI) 0.22-0.53 and RR 0.60, 95% CI 0.36-1.02, respectively. The RR of AEs with anti-TNF therapy was 1.75 (95% CI 0.81-3.79).

Conclusions: Anti-TNF therapy after surgery for CD displays efficacy at preventing endoscopic recurrence for 1-2 years, without increasing the incidence of AEs. However, clinical recurrence was not significantly reduced. The efficacy of postoperative anti-TNF therapy may differ in terms of the outcomes, which include long-term prevention, the avoidance of further surgery, and cost-effectiveness.
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http://dx.doi.org/10.1111/jgh.15288DOI Listing
April 2021

Artificial intelligence-assisted endoscopy changes the definition of mucosal healing in ulcerative colitis.

Dig Endosc 2020 Sep 10. Epub 2020 Sep 10.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan.

The relevance of endoscopic monitoring of ulcerative colitis (UC) has been translated into the new concept of "mucosal healing (MH)" as the therapeutic goal to achieve because a large amount of scientific data have revealed the favorable prognostic value of a healed mucosa in determining the clinical outcome of UC. Recent interest in MH has skewed toward not only endoscopic remission but also histological improvement (so called histological MH). However, we should recognize that there have been no prospectively validated endoscopic scoring systems of UC activity in previous clinical trials. Artificial intelligence (AI)-assisted endoscopy has been developed for gastrointestinal cancer surveillance. Recently, several AI-assisted endoscopic systems have been developed for assessment of MH in UC. In the future, the development of a new endoscopic scoring system based on AI might standardize the definition of MH. Therefore, "The road to an exact definition of MH in the treatment of UC has begun only now".
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http://dx.doi.org/10.1111/den.13825DOI Listing
September 2020

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

Digestion 2020 Sep 4:1-9. Epub 2020 Sep 4.

Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses.

Summary: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.
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http://dx.doi.org/10.1159/000510502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573907PMC
September 2020

Intestinal cancer in patients with Crohn's disease: A systematic review and meta-analysis.

J Gastroenterol Hepatol 2021 Feb 30;36(2):329-336. Epub 2020 Sep 30.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aim: Although surveillance colonoscopy is recommended by several guidelines for Crohn's disease (CD), the evidence is insufficient to support the validity of this recommendation. Moreover, the efficacy of surveillance colonoscopy for anorectal cancer remains unclear. Therefore, we performed a systematic review of cancer in patients with CD before considering the proper surveillance methods.

Methods: We conducted a systematic review and meta-analysis examining the incidence of intestinal cancer and a literature review to clarify the characteristic features of cancer in CD. We performed the systematic literature review of studies published up to May 2019.

Results: Overall, 7344 patients were included in eight studies. The standardized incidence ratios (95% confidence intervals) of colorectal cancer (CRC) and small bowel cancer (SBC) were 2.08 (1.43-3.02) and 22.01 (9.10-53.25), respectively. The prevalence of CRC and SBC was 57/7344 (0.77%) and 17/7344 (0.23%), respectively, during a median follow-up of 12.55 years. Additionally, 54 studies reporting 208 anorectal cancer cases were identified. In patients with anorectal cancer, the prognosis for survival was 2.1 ± 2.3 years, and advanced cancer greater than stage T3 occurred in 46/74 patients (62.1%). Many more reports of anorectal cancer were published in Asia than in Western countries.

Conclusion: Although we were unable to state a recommendation for surveillance for SBC, we should perform cancer surveillance for CRC in patients with CD. However, the characteristics of cancer may differ according to geography or race. We must establish proper and effective surveillance methods that are independently suitable to detect these differences.
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http://dx.doi.org/10.1111/jgh.15229DOI Listing
February 2021

Arteriovenous malformation in pancreas mimicking hypervascular tumor.

JGH Open 2020 Aug 18;4(4):773-774. Epub 2020 Apr 18.

Department of Gastroenterology and Hepatology Sapporo Medical University School of Medicine Sapporo Japan.

Arteriovenous malformation (AVM) is defined as a disease that causes blood flow abnormality due to anastomoses of the arteries and veins. AVM can occur in any gastrointestinal tract, but pancreatic AVM (P-AVM) is very rare. Previous reports demonstrated that contrast-enhanced CT (CECT) typically showed abnormal vascular network in pancreas. We present a 58-year old man with a history of acute pancreatitis. He was referred to our hospital for examination of pancreatic mass. CECT showed a round-shaped hypervascular lesion with a diameter of 8 mm in the head of the pancreas. Selective angiography showed vascular network and early visualization of superior mesenteric vein. We finally diagnosed this case as P-AVM. He underwent duodenum preserving pancreatic head resection. Histological findings confirmed the preoperative diagnosis of P-AVM.
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http://dx.doi.org/10.1002/jgh3.12343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411645PMC
August 2020