Publications by authors named "Kazuhide Higuchi"

495 Publications

Tannin-phytobezoars with Gastric Outlet Obstruction Treated by Dissolution with Administration and Endoscopic Injection of Coca-Cola, Endoscopic Crushing, and Removal (with Video).

Intern Med 2021 Jul 30. Epub 2021 Jul 30.

Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Japan.

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola.
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http://dx.doi.org/10.2169/internalmedicine.8090-21DOI Listing
July 2021

Dysbiosis and liver diseases (Review).

Int J Mol Med 2021 Sep 30;48(3). Epub 2021 Jul 30.

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑8686, Japan.

Dysbiosis, a qualitative and quantitative aberrancy of gut microbiota, has attracted marked attention. At present, advances in molecular biological techniques have made it possible to analyze gut microbiota at the DNA and RNA levels without culturing, and methods such as 16S ribosomal RNA targeting analysis and metagenomic analysis using next‑generation sequencers have been developed. The relationship between gut microbiota and various diseases has been extensively examined. Gut microbiota are essential for the immune system, energy intake and fat storage, and humans use them to build complex immune regulatory mechanisms and to obtain energy from food. The liver is the first organ to be nourished by the portal blood flow of intestinal origin, and liver diseases can be strongly influenced by various factors of intestinal origin, such as intestinal bacteria, bacterial components, and intestinal bacterial metabolites. Rigorous research has revealed that the composition of the gut microbiota is altered and the diversity of bacteria is reduced in liver diseases. Significance of various factors transported to the liver by portal vein blood flow from the intestine has been extensively investigated. Gut microbiota in liver disease can be associated with disease progression regardless of disease etiology and even with carcinogenesis. The relationship between gut microbiota and liver diseases (hepatitis virus‑related diseases, autoimmune liver diseases, alcoholic liver disease, non‑alcoholic fatty liver disease, non‑alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) and the treatments of dysbiosis (antibiotics, prebiotics, probiotics and fecal microbiota transplantation) in liver disease are outlined based on the current evidence.
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http://dx.doi.org/10.3892/ijmm.2021.5016DOI Listing
September 2021

Endoscopic ultrasonography-guided hepaticogastrostomy using a novel laser-cut type partially covered self-expandable metal stent (with video).

Dig Endosc 2021 Jul 28. Epub 2021 Jul 28.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

Endoscopic ultrasonography (EUS)-guided hepaticogastrostomy (HGS) is of clinical benefit in patients with failed endoscopic retrograde cholangiopancreatography (ERCP). However, some endoscopists are concerned about the potential risk of adverse events. Bile peritonitis due to bile leakage through the fistula is one of the possible adverse events following EUS-HGS. Recently, a novel laser-cut type partially covered self-expandable metal stent (PCSEMS), which is a dedicated stent for EUS-HGS, has become available. This stent has an uncovered part, despite it being a laser-cut type stent, along with a flared end. In addition, it uses a 7-Fr stent delivery. Therefore, tract dilation might not be needed to deploy the stent, which might reduce the incidence of stent migration. In this study, the safety of EUS-HGS using this novel laser-cut type PCSEMS was evaluated by assessing technical success, which was defined as successful stent deployment, and clinical success, which was defined as reduction in serum total bilirubin levels by 50% and resolution of symptoms related to biliary tract obstruction within 2 weeks. Five patients with unresectable malignant biliary obstruction underwent EUS-HGS using the novel stent. Stent deployment was successfully performed without tract dilation in four patients, although tract dilation using a balloon catheter was needed in one patient. Clinical success was obtained in all patients, and adverse events including abdominal pain and bile peritonitis were not observed in any of the patients. EUS-HGS without tract dilation can be safely performed using a novel laser-cut type PCSEMS. A prospective comparative study evaluating this stent versus conventional stents is needed to corroborate our results.
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http://dx.doi.org/10.1111/den.14077DOI Listing
July 2021

Dietary intake of vegetables, fruit, and antioxidants and risk of ulcerative colitis: A case-control study in Japan.

Nutrition 2021 Jun 2;91-92:111378. Epub 2021 Jun 2.

Department of Otolaryngology, Head and Neck Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.

Objectives: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk.

Methods: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index.

Results: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively).

Conclusions: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk.
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http://dx.doi.org/10.1016/j.nut.2021.111378DOI Listing
June 2021

EUS-guided antegrade metal stent deployment using a novel fully covered metal stent with a fine gauge stent delivery system (with video).

Endosc Ultrasound 2021 Jul 2. Epub 2021 Jul 2.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.4103/EUS-D-20-00257DOI Listing
July 2021

Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice.

mBio 2021 Jul 6:e0115521. Epub 2021 Jul 6.

Second Department of Internal Medicine, Osaka Medical Collegegrid.444883.7, Takatsuki, Japan.

Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase () and increased ileal fibroblast growth factor 15 () mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.
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http://dx.doi.org/10.1128/mBio.01155-21DOI Listing
July 2021

Antegrade brushing cytology through the EUS-guided pancreatic duct drainage route (with video).

Endosc Ultrasound 2021 Jun 26. Epub 2021 Jun 26.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.4103/EUS-D-20-00258DOI Listing
June 2021

Double puncture of the stomach and duodenum during EUS-guided gallbladder drainage (with video).

Endosc Ultrasound 2021 Jun 26. Epub 2021 Jun 26.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.4103/EUS-D-20-00256DOI Listing
June 2021

Association between Administration of Antithrombotics and Intraperitoneal Hemorrhage in Patients Undergoing Percutaneous Interventions for Liver Diseases.

J Clin Med 2021 Jun 7;10(11). Epub 2021 Jun 7.

2nd Department of Internal Medicine, Osaka Medical College, Takatsuki 5698686, Japan.

Currently, percutaneous interventions are essential for diagnosis and treatment of liver diseases. The most frequent complication of percutaneous interventions is intraperitoneal hemorrhage. Recently, the number of patients with liver diseases on antithrombotics has been increasing. This retrospective cohort study aimed to evaluate the risk factors for intraperitoneal hemorrhage in patients after percutaneous interventions for liver diseases. This study included 1025 patients who underwent percutaneous interventions for liver diseases from April 2015 to March 2020. All interventions were performed using an ultrasound-guided approach. The influence of antithrombotic drug administration in patients, who underwent percutaneous interventions according to the guidelines for the American Association for the Study of Liver Disease, was evaluated. Intraperitoneal hemorrhage after percutaneous interventions was detected by computed tomography. Intraperitoneal hemorrhage occurred in nine patients (0.88%); however, these adverse events were not severe. We compared clinical characteristics between the patients with and without intraperitoneal hemorrhage. Although, there was no difference based on the administration of antithrombotics ( = 0.1961), seven of nine patients who showed intraperitoneal hemorrhage received percutaneous treatments (radio frequency ablation or microwave ablation). Therefore, we divided patients who underwent treatments and liver biopsy and then investigated the influence of antithrombotics on the intraperitoneal hemorrhage. After propensity score matching in each patient group, the administration of antithrombotics was not identified as a risk factor for hemorrhage in patients who underwent interventional treatments and patients who underwent liver biopsy. When the antithrombotics were discontinued, according to the guidelines, it may not increase the risk factor for hemorrhage in patients of liver disease who underwent percutaneous interventions.
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http://dx.doi.org/10.3390/jcm10112527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201393PMC
June 2021

Exploratory Study of the Effectiveness of Granulocyte and Monocyte Adsorptive Apheresis Before Initiation of Steroids in Patients With Active Ulcerative Colitis (EXPECT Study): A Multicenter Prospective Clinical Trial.

Crohns Colitis 360 2020 Oct 23;2(4):otaa073. Epub 2020 Sep 23.

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

Background: Granulocyte and monocyte adsorptive apheresis (GMA) has been used for therapy of steroid-dependent/refractory ulcerative colitis (UC). The aim of this study was to investigate the effectiveness of GMA in UC patients not receiving steroids.

Methods: We conducted a single-arm, open-label, and multicenter prospective clinical trial. UC patients who had insufficient responses to 5-aminosalicylic acid received GMA twice a week for 5 weeks.

Results: The response rate of all patients was 58.2% (39/67). Of the 39 patients who achieved a response, 74.4% achieved endoscopically confirmed mucosal healing.

Conclusions: GMA shows effectiveness in inducing remission in UC patients not receiving steroid.
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http://dx.doi.org/10.1093/crocol/otaa073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797742PMC
October 2020

Pathophysiology and mechanisms of primary sarcopenia (Review).

Int J Mol Med 2021 Aug 29;48(2). Epub 2021 Jun 29.

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑8686, Japan.

Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle‑specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age‑related primary sarcopenia and outlines its pathogenesis and mechanisms.
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http://dx.doi.org/10.3892/ijmm.2021.4989DOI Listing
August 2021

Administration of a standard dose of vonoprazan fumarate delays gastric emptying in Japanese healthy adults: a prospective clinical trial.

J Gastroenterol 2021 Aug 22;56(8):722-731. Epub 2021 Jun 22.

Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan.

Background: There is no established view of how gastric acid suppression affects the time for gastric emptying. Vonoprazan fumarate shows potent and durable gastric acid inhibitory effects, but its effects on gastric emptying have not been studied widely. We investigated the effects of vonoprazan fumarate on gastric emptying and measured serum gastrin and plasma ghrelin levels in healthy adults.

Methods: Ten participants were administered 10 mg vonoprazan fumarate daily for 14 days, then 20 mg vonoprazan fumarate daily for 14 days. The gastric emptying breath test was performed and serum gastrin levels were measured at baseline and after each medication administration period. The protocol was then repeated, with the gastric emptying breath test and serum gastrin and plasma desacyl-ghrelin levels measured at baseline and the end of the medication trial.

Results: Mean serum gastrin levels increased in a dose-dependent manner [baseline: 104.7 ± 50.4, after 10 mg protocol: 328 ± 123.8, after 20 mg protocol: 555 ± 378.8 (pg/mL, mean ± standard deviation), p = 0.0008]. There was a significant difference between the gastric emptying breath test Tmax at baseline and just after the 20 mg protocol (baseline: 45.5 ± 15.3, after 20 mg protocol: 60.5 ± 19.6 min, p = 0.0418). Plasma desacyl-ghrelin levels increased significantly just after the 20 mg protocol compared to those at baseline [baseline: 222.3 ± 106.4, after 20 mg protocol: 366.2 ± 178.6 (fmol/mL), p = 0.0008].

Conclusions: In healthy adults, 14 days of vonoprazan fumarate administration at 20 mg/day delayed gastric emptying.

Trial Registration: This clinical trial was registered in the University hospital Medical Information Network Clinical Trial Registry (Trial No. UMIN000039199 and UMIN000042969).
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http://dx.doi.org/10.1007/s00535-021-01801-3DOI Listing
August 2021

Prospective multicenter evaluation of moving cell metallic stents in endoscopic multiple stent deployment for hepatic hilar obstruction.

J Hepatobiliary Pancreat Sci 2021 Jun 10. Epub 2021 Jun 10.

TSOZ Pancreatobiliary Study Group, Osaka, Japan.

Background And Aim: Bilateral stent deployment for malignant biliary obstruction (MHBO) can be achieved using side-by-side (SBS) or stent-in-stent (SIS) procedures. Compared with SBS techniques, the procedural steps of SIS are technically complex due to the necessity of introducing the delivery system into a contralateral biliary tract through the mesh of the SEMS. To overcome this issue, a novel uncovered SEMS, the HILZO Moving Cell Stent (MCS) has been released. The present study examined the technical feasibility of treating MHBO using bilateral deployment of this novel stent without dilating the mesh of the first stent to achieve insertion of the second stent within a single session, using a prospective, multicenter setting.

Method: The primary outcome in the present study was the technical success rate. Technical success was defined as deployment of bilateral MCSs into two or more biliary tracts using SIS without a dilation device in a single-session.

Results: A total of 27 patients with complications of MHBO were enrolled in this study. Bilateral SIS using two MCS was successfully performed in 23 patients without using dilation devices among 27 patients (initial technical success rate; 85.2%). Median time to recurrent biliary obstruction (TRBO) was 271 days. Stent dysfunction was observed in 12 patients (44.4%), and re-intervention was successfully performed in all patients without one patient who instead received best supportive care.

Conclusions: The SIS technique using MCS without dilation of the mesh may be technically feasible and safe. In addition, this may be useful for re-intervention. Further comparative randomized trials are needed.
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http://dx.doi.org/10.1002/jhbp.1009DOI Listing
June 2021

Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy.

Regen Ther 2021 Dec 21;18:97-101. Epub 2021 May 21.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Introduction: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs.

Methods: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients.

Results: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered.

Conclusion: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
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http://dx.doi.org/10.1016/j.reth.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165289PMC
December 2021

Effect of a proton-pump inhibitor on intestinal microbiota in patients taking low-dose aspirin.

Eur J Clin Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki City, Osaka, 569-8686, Japan.

Background And Aim: Low-dose aspirin (LDA) administration prevents cerebral infarction and myocardial infarction, but many studies found an association with mucosal injury. Proton-pump inhibitors (PPIs) can prevent gastric and duodenal mucosal damage, but they may exacerbate small-intestinal mucosal injury by altering the microbiota. We aimed to assess the effect of PPIs on the intestinal flora of LDA users.

Methods: Thirty-two recruited patients, who received LDA (100 mg/day) but did not take PPIs, were divided into 15 patients additionally receiving esomeprazole (20 mg/day) and 17 patients additionally receiving vonoprazan (10 mg/day). On days 0, 30, 90, and 180, the microbiota of each patient was examined by terminal restriction fragment length polymorphism analysis, and the serum gastrin, hemoglobin, and hematocrit levels were measured.

Results: Additional PPI administration increased the proportion of Lactobacillales in the microbiota of LDA users. This trend was more prevalent in the vonoprazan group (p < 0.0001) than in the esomeprazole group (p = 0.0024). The Lactobacillales proportion was positively correlated with the gastrin level (r = 0.5354). No significant hemoglobin or hematocrit level reduction was observed in subjects receiving LDA with additional PPI.

Conclusions: Additional PPI administration increased the Lactobacillales proportion in the microbiota of LDA users. The positive correlation between the gastrin level and the proportion of Lactobacillales suggested that the change in the intestinal flora was associated with the degree of suppression of gastric acid secretion. Additional oral PPI did not significantly promote anemia, but the risk of causing PPI-induced small-intestinal mucosal injury in LDA users should be considered.
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http://dx.doi.org/10.1007/s00228-021-03167-0DOI Listing
June 2021

Exacerbation of liver dysfunction in non-alcoholic steatohepatitis patients during the coronavirus disease 2019 (COVID-19) pandemic.

J Clin Biochem Nutr 2021 May 3;68(3):243-245. Epub 2020 Dec 3.

2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan.

Many people were forced to stay at home, including non-alcoholic steatohepatitis (NASH) patients, however it is unclear how this home-life has affected the prognosis of NASH. In this study, we examined the influences of living at home during the coronavirus disease 2019 (COVID-19) pandemic NASH patients. In this study, we compared the clinical parameters of NASH patients without COVID-19 infection 3 months before with those 3 months after the declaration of a state of emergency. In the results, the changes of aspartate transaminase and alanine aminotransferase in the 3 months before (aspartate transaminase, -3.6 ± 13.8 U/L; alanine aminotransferase, -6.8 ± 19.5 U/L) was significantly exacerbated in the 3 months after (aspartate transaminase, 2.3 ± 7.5 U/L; alanine aminotransferase, 1.7 ± 10.4 U/L). Furthermore, the changes of the fibrosis-4 index in the 3 months before (-0.27 ± 0.84) was also significantly exacerbated in the 3 months after (0.38 ± 0.96). In conclusion, liver dysfunctions in NASH patients were exacerbated due to the emergency declaration and outing restriction which accompanied COVID-19.
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http://dx.doi.org/10.3164/jcbn.20-136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129973PMC
May 2021

Clinical impact of recombinant thrombomodulin administration on disseminated intravascular coagulation due to severe acute cholangitis (Recover-AC study).

J Hepatobiliary Pancreat Sci 2021 May 22. Epub 2021 May 22.

Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

Background And Aim: Recombinant thrombomodulin (rhTM) is potentially effective in the treatment of disseminated intravascular coagulation (DIC). Several studies related to drugs for the treatment of acute cholangitis have shown negative results in improvement of overall survival (OS) with rhTM. The aim of this multicenter study was to evaluate the clinical effectiveness of rhTM in patients with acute cholangitis and sepsis-induced DIC who underwent biliary drainage.

Methods: A total of 284 consecutive patients, who were complicated with sepsis-induced DIC due to severe acute cholangitis, were included (rhTM group, n = 173; non-rhTM, n = 111) in this study. The primary outcome was the DIC resolution rate at 7 days after starting treatment. The 28-day survival rate was secondarily evaluated.

Results: DIC scores in the rhTM group improved significantly compared with the non-rhTM group on day 7 (P = .020). According to multivariate analysis, etiology of cholangitis (malignant, HR 2.28), rhTM (non-administration, HR 4.13), and DIC score (≥5, HR 2.46) were significant factors associated with failed DIC resolution on day 7. Propensity score matching created 103 matched pairs. Survival rate at day 28 was significantly higher in rhTM group (94.3%) compared with non-rhTM group (82.6%; P = .048) after propensity score matching. rhTM (non-administration, HR 2.870), DIC score (≥5, HR 2.751), and APACHE II score (≥20, HR 9.310) were significant factors associated with decreasing survival rate at day 28.

Conclusion: In conclusion, rhTM seemed to improve patient survival, but future studies should only include patients with benign or malignant disease and should be performed according to APACHE II scores.
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http://dx.doi.org/10.1002/jhbp.998DOI Listing
May 2021

Moving scope technique for guidewire insertion during endoscopic ultrasound-guided hepaticogastrostomy.

Dig Endosc 2021 Jul 10;33(5):e109-e110. Epub 2021 May 10.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.1111/den.13993DOI Listing
July 2021

Obesity and Liver Cancer in Japan: A Comprehensive Review.

Anticancer Res 2021 May;41(5):2227-2237

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.

Lifestyle-related factors play a major role in the development of cancer. In recent years, obesity has become widespread in the world and has attracted attention not only as a cause of diabetes mellitus and atherosclerotic diseases but also as a factor in carcinogenesis. In Japan, the number of obesity-related malignancies has been increasing with the westernization of lifestyle. On the other hand, it is estimated that there are more than 10 million nonalcoholic fatty liver disease (NAFLD) patients in Japan. NAFLD is classified into simple fatty liver and nonalcoholic steatohepatitis (NASH), and 10-20% of NASH patients will progress to liver cirrhosis and 2-3% of them will develop hepatocellular carcinoma (HCC) per year. Research interest in metabolism-associated liver cancer has been increasing in recent years. Here in this review, we will comprehensively summarize the current knowledge with regard to the relationship between obesity and HCC in Japan.
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http://dx.doi.org/10.21873/anticanres.14999DOI Listing
May 2021

Sarcopenia and Frailty in Liver Cirrhosis.

Life (Basel) 2021 Apr 27;11(5). Epub 2021 Apr 27.

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-8686, Japan.

Skeletal muscle is the largest organ in the body, and skeletal muscle atrophy results from a shift in the balance of protein synthesis and degradation toward protein breakdown. Primary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to aging, and secondary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to underlying diseases. Liver cirrhosis (LC) is one of the representative diseases which can be complicated with secondary sarcopenia. Muscle mass loss becomes more pronounced with worsening liver reserve in LC patients. While frailty encompasses a state of increased vulnerability to environmental factors, there is also the reversibility of returning to a healthy state with appropriate intervention. Several assessment criteria for sarcopenia and frailty were proposed in recent years. In 2016, the Japan Society of Hepatology created assessment criteria for sarcopenia in liver disease. In Japan, health checkups for frailty in the elderly aged 75 years or more started in April 2020. Both sarcopenia and frailty can be adverse predictors for cirrhotic patients. In this review article, we will summarize the current knowledge of sarcopenia and frailty in LC patients.
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http://dx.doi.org/10.3390/life11050399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146021PMC
April 2021

Hepatic F4/80 CD11b CD68 cells influence the antibacterial response in irradiated mice with sepsis by Enterococcus faecalis.

J Leukoc Biol 2021 05;109(5):943-952

2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan.

Gut-associated sepsis is a major problem in patients undergoing abdominal radiation therapy; the majority of pathogens causing this type of sepsis are translocated from the gut microbiota. While treating sepsis, bacterial clearance must be achieved to ensure patient survival, and the hepatic immune response is responsible for this process. In particular, Kupffer cells play a crucial role in the hepatic immune response against infectious agents. Recently, two populations of Kupffer cells have been described: liver-resident macrophages (Mϕ) (F4/80 CD11b CD68 cells) and hepatic Mϕ derived from circulating monocytes (F4/80 CD11b CD68 cells). We examined the properties of both types of hepatic Mϕ obtained from irradiated and normal mice and their role in sepsis. Hepatic F4/80 CD11b CD68 cells from both normal and irradiated mice did not show any antibacterial activity. However, F4/80 CD11b CD68 cells from normal mice behaved as effector cells against sepsis by Enterococcus faecalis, although those from irradiated mice lost this ability. Moreover, hepatic F4/80 CD11b CD68 cells from normal infected mice were shown to be IL-12 IL-10 CD206 CCL1 (considered M1Mϕ), and hepatic F4/80 CD11b CD68 cells from the same mice were shown to be IL-12 IL-10 CD206 CCL1 (considered M2aMϕ). When normal mice were exposed to radiation, hepatic F4/80 CD11b CD68 cells altered their phenotype to IL-12 IL-10 CD206 CCL1 (considered M2bMϕ), independent of infection, but hepatic F4/80 CD11b CD68 cells remained IL-12 IL-10 CD206 CCL1 (M2aMϕ). In addition, hepatic F4/80 CD11b CD68 cells from irradiated mice acquired antibacterial activity upon treatment with CCL1 antisense oligodeoxynucleotides. Therefore, the characteristics of hepatic F4/80 CD11b CD68 cells play a key role in the antibacterial response against gut-associated sepsis.
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http://dx.doi.org/10.1002/JLB.4A0820-550RRDOI Listing
May 2021

Technical Review of Developments in Endoscopic Ultrasound-Guided Hepaticogastrostomy.

Clin Endosc 2021 Apr 26. Epub 2021 Apr 26.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

Endoscopic ultrasound-guided biliary drainage has been developed as an alternative method for biliary drainage. EUS-guided hepaticogastrostomy (EUS-HGS) can be attempted via the trans-gastric route. These procedures are technically complex for two reasons. First, puncture of the intrahepatic bile duct via the trans-gastric route can be more difficult than that by other approaches because of the small diameter of the target site, and guidewire insertion or manipulation is challenging during EUS-HGS. Second, critical adverse events, such as stent migration into the abdominal cavity, could occur because of the greater mobility of the stomach compared to the duodenum. Therefore, endoscopists should be cautious when performing EUS-HGS. An advantage of EUS-HGS is that it can be performed in patients with complications such as duodenal bulb obstruction or surgically altered anatomy. Recent advances in technique and improvements in devices and stents for EUS-HGS have shown promise for improving the technical success rate of EUS-HGS and reducing the rate of adverse events. However, endoscopists should remain aware of the possibility of critical adverse events such as stent migration.
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http://dx.doi.org/10.5946/ce.2021.020-KDDWDOI Listing
April 2021

Novel adsorptive type apheresis device Immunopure for ulcerative colitis from clinical perspectives based on clinical trials: Japan and Europe.

Ther Apher Dial 2021 Aug 6;25(4):432-436. Epub 2021 May 6.

Division of Gastroenterology and Hepatology, Shin-Koga Hospital, Kurume, Japan.

Several adsorptive type devices for ulcerative colitis are used for the induction of remission in patients with active severe disease worldwide. In 2020, the novel apheresis device Immunopure for ulcerative colitis was launched in Japan. Immunopure, like the polyethylene terephthalate column, uses polyarylate, a type of polyester resin, as the adsorbent. Similar to the cellulose acetate column, Immunopure is filled with adsorbent beads and expected to provide ease of use, with minimal risk of column clogging. Immunopure adsorbs leukocytes and platelets, especially activated platelets and platelet-leukocyte aggregates. In this article, the capability of Immunopure is evaluated from clinical perspective based on a clinical trial in Japan/Europe. As a result, Immunopure is comparable to other products in clinical effectiveness and indicated for the treatment of patients with refractory moderate ulcerative colitis, making it highly useful in clinical practice.
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http://dx.doi.org/10.1111/1744-9987.13661DOI Listing
August 2021

Jumping technique for guidewire manipulation within an intrahepatic bile duct during EUS-guided biliary drainage (with video).

Endosc Ultrasound 2021 Apr 21. Epub 2021 Apr 21.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.4103/EUS-D-20-00194DOI Listing
April 2021

Recanalization of a distorted duodenal metal stent using a fine-gauge electrocautery dilator.

Endoscopy 2021 Apr 20. Epub 2021 Apr 20.

Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

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http://dx.doi.org/10.1055/a-1408-0860DOI Listing
April 2021

Pharmacokinetics of Dexamethasone when Administered with Fosaprepitant for Chemotherapy-Induced Nausea and Vomiting and Differences in Dose-Dependent Antiemetic Effects.

Asian Pac J Cancer Prev 2021 Mar 1;22(3):871-877. Epub 2021 Mar 1.

Second Department of Internal Medicine, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.

Background: Fosaprepitant, an NK1 receptor antagonist, inhibits and induces cytochrome P450 3A4 (CYP3A4) as its substrate. Contrarily dexamethasone is metabolized by CYP3A4. Therefore, in combination therapy wherein both agents interact with each other, it is recommended that the dexamethasone dose be reduced in the first two days. Thus far, there are only a few studies on the optimum dose of dexamethasone after day 3. Thus, we aimed to determine the pharmacokinetics of dexamethasone on day3 when administered together with fosaprepitant and investigate the dose-dependent differences in its antiemetic effect in patients with cancer.

Methods: Twelve patients with esophageal, stomach, or lung cancer received primary highly emetogenic chemotherapy (HEC). We intravenously administered 9.9 mg and 6.6 mg of dexamethasone on days 1 and 2, respectively, and 6.6 mg or 13.2 mg on day 3 together with the administration of 150 mg fosaprepitant and 0.75 mg palonosetron. We assessed the pharmacokinetics of dexamethasone on day 3 by dose and examined the dose-dependent antiemetic effect.

Results: No differences were observed in the time-to-maximum concentration and blood half-life of dexamethasone between patient groups that received dexamethasone at doses of 6.6 mg and 13.2 mg. In contrast, the area under the blood concentration-time curve and the maximum concentration of dexamethasone correlated with its dose. Moreover, the blood dexamethasone concentration on day 3 increased by twofold after the administration of a higher dose than after a lower dose. The severity of nausea in the delayed phase significantly decreased in a dose-dependent manner.

Conclusion: Administration of a higher dexamethasone dose on day 3 improved the antiemetic effect of the combined regimen in patients with cancer who underwent HEC.
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http://dx.doi.org/10.31557/APJCP.2021.22.3.871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286666PMC
March 2021

The role of advanced endoscopy in the management of inflammatory digestive diseases (upper gastrointestinal tract).

Dig Endosc 2021 Mar 27. Epub 2021 Mar 27.

Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

The Japan Gastroenterological Endoscopy Society held four serial symposia between 2019 and 2020 on the state-of-the-art of issues related to upper GI inflammatory diseases. This review discusses some of the topics addressed in these symposia. The papers regarding nonerosive reflux disease, recent improvements in intraesophageal pH-impedance monitoring and endoscopic diagnosis using image-enhanced endoscopy have been published. Many publications have addressed its usefulness in endoscopic treatment of gastroesophageal reflux disease such as anti-reflux mucosectomy. In the management of eosinophilic esophagitis, since the symptoms are subjective, objective indicators have been sought, and ultrasonography and high-resolution manometry may be useful tools for evaluation. The natural course of this condition, especially of asymptomatic cases, is not well clarified. Some newly developed anti-acid or anti-inflammatory medicines are now under investigation. With regard to autoimmune gastritis, because of widespread medical examinations, diagnosis of asymptomatic cases has been increasing. Recently, its endoscopic characteristics have become clear and the natural history of these conditions is being elucidated. The Kyoto Classification of Gastritis has been reported to be useful not only for Helicobacter pylori diagnosis but also for identification of risks of gastric cancer. Its usefulness is now recognized in Asia and Europe.
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http://dx.doi.org/10.1111/den.13982DOI Listing
March 2021

Experimental study of loop shape using 0.025-inch ERCP guidewires (with videos).

Endosc Int Open 2021 Mar 19;9(3):E427-E437. Epub 2021 Feb 19.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

 Duct penetration by the guidewire sometimes occurs during endoscopic retrograde cholangiography, which might lead to adverse events such as acute pancreatitis. To prevent duct penetration, making a loop shape with the guidewire might provide a useful technique. The aim of this experimental study was thus to evaluate which types of guidewire can most easily form a loop shape. This experimental study evaluated six guidewires (0.025-inch, angle type): MICHISUJI; VisiGlide 2; Jagwire; Pathcorse; RevoWave-α UltraHard 2; and M-through. Flexibility of the tip, shaft stiffness, and the ability to form a loop were evaluated for each type in an ex vivo model. Deformation behavior was also recorded on video, and factors suitable for making a loop shape in each guidewire were evaluated.  Flexibility and stiffness of each guidewire differed significantly. During an experimental study regrading deformation behavior before forming a loop shape, maximum load was lower for MICHISUJI (6.8 g) than for other guidewires (Jagwire [11.3 g], M-through [12.9 g], VisiGlide 2 [12.9 g], Revowave [21 g], and Pathcorse [25.4 g]). Mean time required to achieve a loop shape was as follows: MICHISUJI, 6.2 seconds; M-through, 8.7 seconds; VisiGlide 2, 11.0 seconds; and Revowave, 7.1 seconds.  In conclusion, characteristics of flexibility and stiffness among guidewires were significantly different in the ex-vivo study. In the experimental study regrading deformation behavior until achieving a loop shape, maximum load also differed. To evaluate whether guidewires easily form a loop shape, clinical study is needed.
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http://dx.doi.org/10.1055/a-1319-0915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895657PMC
March 2021

Clinical evaluation of physician-controlled guidewire manipulation during endoscopic ultrasound-guided hepaticogastrostomy (with video).

Endosc Int Open 2021 Mar 19;9(3):E395-E400. Epub 2021 Feb 19.

2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan.

Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (HGS) may be most complex because of the EUS-guided biliary drainage procedure and variations in the course of the intrahepatic bile duct compared with the common bile duct (CBD). Appropriate guidewire insertion is essential. Physician-controlled guidewire manipulation (PCGW) might improve technical success rates of bile duct cannulation. The present study aimed to determine the technical feasibility and safety of PCGW during EUS-HGS. A total of 122 consecutive patients who were scheduled to undergo EUS-HGS between October 2017 and April 2019 were prospectively registered. The primary endpoint was the technical success rate of guidewire insertion into the CBD or hepatic hilum. Guidewire insertion was considered to have failed if the HGS assistant failed to achieve manipulation. The intrahepatic bile duct was successfully punctured in 120 of 122 patients. During guidewire insertion by the HGS assistant, guidewire fracture was observed in one patient. The guidewire was successfully inserted into the biliary tract and manipulated by the HGS assistant in 96 patients. PCGW was thus attempted for the remaining 23 patients. The guidewire was inserted by PCGW in all 23 patients, improving the technical success rate for guidewire insertion from 80 % to 100 %. After tract dilation, we deployed covered metal stents and plastic stents in 117 and two patients, respectively. The overall technical success rate for EUS-HGS was 97.5 % (119/122). Adverse events comprising bile peritonitis or leakage developed in five patients. PCGW might contribute to improving the success rate of EUS-HGS.
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http://dx.doi.org/10.1055/a-1336-3132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895653PMC
March 2021
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