An Analysis of Delayed Bleeding in Cases of Colorectal Endoscopic Submucosal Dissection Due to Types of Direct Oral Anticoagulants in Japan.

BACKGROUND & AIMS: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin. METHODS: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated. RESULTS: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively. CONCLUSIONS: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin.

Risk Factors of Delayed Bleeding After Cold Snare Polypectomy for Colorectal Polyps: A Multicenter Study.

BACKGROUND: Delayed bleeding (DB) rarely occurs after cold snare polypectomy (CSP) for colorectal polyps, but no large-scale studies have investigated this. The present study evaluated the rate, characteristics, and risk factors of DB of CSP. METHODS: We conducted a multicenter retrospective study at 10 Japanese institutions. A total of 18,007 patients underwent CSP for colorectal polyps ≤ 10 mm in size from March 2015 to September 2019, and cases of DB (DB group) were analyzed for the rate, antithrombotic drugs, polyp size, morphology, location, and risk factors. As a control, 269 non-bleeding cases (non-DB group) with 606 polyps who underwent CSP at the same 10 facilities in the 2-week study period were extracted. RESULTS: We analyzed 26 DB cases with 28 lesions, and the total DB rate was 0.14% (26/18,007). The DB group had significantly higher rates of using antiplatelets (42.3% vs. 13.0%, p < 0.001) and anticoagulants (19.2% vs. 2.6%, p = 0.002), and significantly higher rates of polyp size ≥ 5 mm (67.9% vs. 45.2%, p = 0.015), rectal lesion (25.0% vs. 6.6%, p = 0.003), and polypoid lesion (89.3% vs. 55.3%, p < 0.001) than the non-DB group. A multivariate analysis (odds ratio; 95% confidence interval) for patient characteristics showed antiplatelet use (4.521; 1.817-11.249, p = 0.001) and anticoagulant use (7.866; 20.63-29.988, p = 0.003) as independent risk factors for DB. Polyp size ≥ 5 mm (3.251; 1.417-7.463, p = 0.005), rectal lesion (3.674; 1.426-9.465, p = 0.007), and polypoid lesion (7.087; 20.81-24.132, p = 0.002) were also risk factors for lesion characteristics. CONCLUSIONS: The rate of DB was 0.14% and antithrombotic drug use, polyp size, location, and morphology were related to it.

Risk of lymph node metastasis after endoscopic treatment for rectal NETs 10 mm or less.

PURPOSE: For rectal neuroendocrine tumors (NETs) ≤ 10 mm, endoscopic resection is a standard treatment. However, there is no consensus whether additional surgery should be performed for patients at risk of lymph node metastasis (LNM) after endoscopic resection. The purpose of this study was to analyze the results of endoscopic resection and additional surgery of rectal NETs, thereby clarify the characteristics of cases with LNM. METHODS: This study was a multicenter retrospective cohort study conducted at 12 Japanese institutions. A total of 132 NETs ≤ 10 mm were analyzed regarding various therapeutic results. A comparative analysis was performed by dividing the cases into two groups that underwent additional surgery or not. Furthermore, the relationship between tumor size and LNM was examined. RESULTS: The endoscopic treatments were 12 endoscopic mucosal resections (EMR), 58 endoscopic submucosal resections with ligation (ESMR-L), 29 precutting EMRs, and 33 endoscopic submucosal dissections (ESD). The R0 resection rates of EMR were 41.7%, and compared to this rate, other three treatments were 86.2% (p < 0.001), 86.2% (p = 0.005), and 97.0% (p < 0.001), respectively. There were 41 non-curative cases (31.1%), and 13 had undergone additional surgery. Then, LNM was observed in 4 of the 13 patients, with an overall rate of LNM of 3.0% (4/132). The rate of positive lymphatic invasion and the rate of LNM by tumor size ≤ 6 mm and 7-10 mm were 9.7 vs. 15.4% (p = 0.375) and 0 vs. 10.3% (p = 0.007). CONCLUSIONS: A multicenter study revealed the priority of each endoscopic resection and the low rate of LNM for rectal NETs ≤ 6 mm.

The Efficacy of Short-Duration Polyethylene Glycol plus Electrolytes for Improving Bowel Preparation of Colonoscopy in Patients with Chronic Constipation.

MATERIALS AND METHODS: This multicenter retrospective study was conducted from September 2019 to September 2020 at 5 related institutions among patients ≥ 20 years old diagnosed with chronic constipation whose previous colonoscopic BP had had a fair or poor Aronchick score. Two or four sachets of PEG+E (13.7 or 27.4 g/day) were prescribed for 1 week before colonoscopy. We analyzed the rate of improvement in BP, effect-related factors, spontaneous bowel movements (SBMs), stool consistency, improvement of constipation symptoms, and adverse events. RESULTS: We evaluated 106 cases (56 males) with an average age of 69.5 ± 9.4 years old (≤74 years old: 68 cases, ≥75 years old: 38 cases). The improvement rate of BP was 72.6%, and the insertion time and pain score also improved. A performance status of 1 or 2 was associated with poor BP. SBMs (times/week) increased from 4.0 ± 1.9 to 6.1 ± 2.6 (p < 0.001). The overall improvement rates of SBMs, stool consistency, symptoms of constipation, and rate of adverse events were 58.5%, 90.6%, 59.4%, and 6.6%, respectively, showing no significant differences with regard to age or gender. CONCLUSIONS: Short-duration PEG+E was effective for improving poor BP and chronic constipation.

The Efficacy and Safety of Elobixibat for the Elderly with Chronic Constipation: A Multicenter Retrospective Cohort Study.

MATERIALS AND METHODS: This was a multicenter retrospective cohort study. The subjects were patients aged ≥20 years treated for chronic constipation from May 2018 to November 2019 at 12 related institutions. Patients were divided into ≤74 years and ≥75 years old. Elobixibat at 10 mg/day was prescribed for two weeks. We then analyzed the discontinuation due to ineffectiveness, change of spontaneous bowel movements (SBM), stool consistency, the time until the first SBM, adverse events, and effect-related factors. RESULTS: There were 140 cases (61 males) evaluated, with an average age of 72.1 ± 13.6 years (≤74 years: 71 cases; ≥75 years: 69 cases). The discontinuation rate was 7.9%. The SBM (times/week) increased from 2.86 to 6.08 (p < 0.001). The overall SBM improvement rate was 74.0% (≤74 years: 78.2% vs. ≥75 years: 68.9%, p = 0.31; male: 75.0% vs. female: 73.3%, p = 0.78). The overall improvement rate of stool consistency was 59.6% (≤74 years: 62.9%, ≥75 years: 56.1%, p = 0.42). The time until the first SBM (hours) for those ≤74 years and ≥75 years was 17.2 ± 14.3 and 11.2 ± 8.4 (p = 0.04). Adverse event rates for those ≤74 years and ≥75 years were 28.2% and 10.1% (p < 0.01). There were no significant effect-related factors for gender, age, and use of laxatives. CONCLUSIONS: Short-period elobixibat is shown to be effective also for the elderly and male.

Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice.

BACKGROUND AND AIMS: Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4-/y) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model. MATERIALS AND METHODS: Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4-/y male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues. RESULTS: PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4-/y mice were significantly higher compared to those of WT mice. Specifically, PRDX4-/y mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4-/y compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4-/y compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4-/y compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4-/y than WT mice, which was consistent with severe ER stress under PRDX4 deficiency. CONCLUSION: Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4-/y than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation.

[A case of liver Mycobacterium avium complex syndrome, diagnosed by liver biopsy].

A man in his 70s was referred to our hospital for evaluation of low-grade fever, weight loss, and liver dysfunction. Serological tests for viral hepatitis or autoimmune diseases were negative. No significant findings were observed on whole-body computed tomography (CT). Histopathologic examination of a liver biopsy sample revealed a non-caseating granuloma with acid-fast bacillus using the Ziehl-Neelsen stain. Serum Mycobacterium avium complex (MAC) antibody was positive. We started treatment for pulmonary MAC disease. His clinical condition and liver function improved within two months. He was diagnosed with liver MAC disease.

[A recurrent gastric cancer with peritoneal metastasis 15 years after distal gastrectomy successfully treated with S-1 and weekly intravenous and intraperitoneal injections of Paclitaxel].

Fifteen years after receiving a distal gastrectomy for advanced gastric cancer, a 70-year-old woman was admitted to our hospital because of abdominal fullness due to ascites. Although cytological examination showed adenocarcinoma cells in the fluid, no examination revealed the primary lesion. Peritoneal metastasis was detected via immunohistochemistry using the cell block technique. After chemotherapy failure (S-1 plus CDDP, weekly PTX, and S-1 plus DOC), the patient received S-1 and weekly intravenous and intraperitoneal injections of PTX. The ascites decreased, and she has been doing well. Our experience with this case suggests that S-1 and weekly intravenous and intraperitoneal injections of PTX is a promising means of treating gastric cancer with peritoneal metastasis.

Preventive effect of agaro-oligosaccharides on non-steroidal anti-inflammatory drug-induced small intestinal injury in mice.

BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used in clinical medicine, cause erosion, ulcers, and bleeding in the gastrointestinal tract. No effective agent for the prevention and treatment of small intestinal injury by NSAIDs has been established. This study investigates the effects of agaro-oligosaccharides (AGOs) on NSAID-induced small intestinal injury in mice. METHODS: Mice were treated with indomethacin, an NSAID, to induce intestinal injury. The respective degrees of mucosal injury of mice that received AGO and control mice were compared. Heme oxygenase-1 (HO-1) expression using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were measured. The expression of keratinocyte chemoattractant (KC) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS: AGO administration induced HO-1 expression in mouse small intestinal mucosa. Induction was observed mainly in F4/80 positive macrophages. The increased ulcers score, myeloperoxidase activity, and KC expression by indomethacin were inhibited by AGO administration. Conversely, HO inhibitor cancelled AGO-mediated prevention of intestinal injury. In mouse peritoneal macrophages, AGOs enhanced HO-1 expression and suppressed lipopolysaccharide-induced KC expression. Furthermore, AGOs enhanced the expressions of alternatively activated macrophage markers arginase-1, mannose receptor-1, and chitinase 3-like 3. CONCLUSIONS: Results suggest that oral administration of AGOs prevents NSAID-induced intestinal injury.

MDR1 is related to intestinal epithelial injury induced by acetylsalicylic acid.

BACKGROUND/AIMS: Although the cytotoxicity of aspirin against the intestinal epithelium is a major clinical problem, little is known about its pathogenesis. We assessed the involvement of Multi Drug Resistance (MDR) 1 in intestinal epithelial cell injury caused by aspirin using MDR1 gene-transfected Caco2 cells. METHODS: Caco2 cells were treated with various concentrations of aspirin for 24 h. After treatment of Caco2 cells with verapamil, a specific inhibitor of MDR1, we assessed the extent of cell injury using a WST-8 assay at 24 h after aspirin-stimulation. We performed the same procedure in MDR1 gene-transfected Caco2 cells. To determine the function of MDR1 in the metabolism of aspirin, flux study was performed using (14)C-labeled aspirin. RESULTS: The level of aspirin-induced cell injury was higher in verapamil-treated Caco2 cells than in control cells and was less serious in MDR1-transfected Caco2 cells than in control vector-transfected cells. The efflux of (14)C-labeled aspirin was higher in verapamil-treated Caco2 cells than in control cells. CONCLUSION: These data suggest that aspirin effux occurs through the MDR1 transporter and that the MDR1 transporter is involved in the pathogenesis of aspirin-induced cell injury.

Role of metallothionein in murine experimental colitis.

Metallothioneins (MTs) are a family of cysteine-rich low molecular-weight proteins that can act as reactive oxygen species scavengers. Although it is known that the induction of MT expression suppresses various inflammatory disorders, the role of MTs in intestinal inflammation remains unclear. In this study, we investigated the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of the MT-I/II genes. Acute colitis was induced by 2% DSS in male MT-I/II double knockout (MT-null) and C57BL/6 (wild-type) mice. The disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency and intestinal bleeding. Histology, colon length, myeloperoxidase (MPO) activity and colonic mRNA expression and the concentration of inflammatory cytokines were evaluated by real-time-PCR and enzyme-linked immunosorbent assay (ELISA). The localization of MTs and macrophages was determined by immunohistological and immunofluorescence staining. To investigate the role of MTs in macrophages, peritoneal macrophages were isolated and their responses to lipopolysaccharide were measured. Following DSS administration, the DAI score increased in a time-dependent manner and was significantly enhanced in the MT-I/II knockout mice. Colonic MPO activity levels and inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17] production increased following DSS administration, and these increases were significantly enhanced in the MT-I/II knockout mice compared with the wild-type mice. MT-positive cells were detected in the lamina propria and submucosal layer by immunohistochemical and immunofluorescence staining, and were mainly co-localized in F4/80-positive macrophages. The production of inflammatory cytokines (TNF-α, IFN-γ and IL-17) from isolated peritoneal macrophages increased following lipopolysaccharide stimulation, and these increases were significantly enhanced in the macrophages obtained from the MT-I/II knockout mice. These data indicate that MTs play an important role in the prevention of colonic mucosal inflammation in a mouse model of DSS-induced colitis, thus suggesting that endogenous MTs play a protective role against intestinal inflammation.

Hemin ameliorates indomethacin-induced small intestinal injury in mice through the induction of heme oxygenase-1.

BACKGROUND AND AIM: Although non-steroidal anti-inflammatory drugs can induce intestinal injury, the mechanisms are not fully understood, and treatment has yet to be established. Heme oxygenase-1 (HO-1) has recently gained attention for anti-inflammatory and cytoprotective effects. This study aimed to investigate the effects of hemin, an HO-1 inducer, on indomethacin-induced enteritis in mice. METHODS: Enteritis was induced by single subcutaneous administration of indomethacin (10 mg/kg) in male C57BL/6 mice. Hemin (30 mg/kg) was administered by intraperitoneal administration 6 h before indomethacin administration. Mice were randomly divided into four groups: (i) sham + vehicle; (ii) sham + hemin; (iii) indomethacin + vehicle; or (iv) indomethacin + hemin. Enteritis was evaluated by measuring ulcerative lesions. Myeloperoxidase activity was measured as an index of neutrophil accumulation. The mRNA expression of inflammatory cytokines and chemokines, such as tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and keratinocyte chemoattractant, were analyzed by real-time polymerase chain reaction. RESULTS: The area of ulcerative lesions, myeloperoxidase activity, and mRNA expression of inflammatory cytokines and chemokines were significantly increased in mice administrated with indomethacin compared with vehicle-treated sham mice. Development of intestinal lesions, increased levels of myeloperoxidase activities, and mRNA expressions of inflammatory cytokines and chemokines were significantly suppressed in mice treated with hemin compared with vehicle-treated mice. Protective effects of hemin were reversed by co-administration of tin protoporphyrin, an HO-1 inhibitor. CONCLUSIONS: Induction of HO-1 by hemin inhibits indomethacin-induced intestinal injury through upregulation of HO-1. Pharmacological induction of HO-1 may offer a novel therapeutic strategy to prevent indomethacin-induced small intestinal injury.

Acetyl salicylic acid induces damage to intestinal epithelial cells by oxidation-related modifications of ZO-1.

Acetyl salicylic acid (ASA) is one of the most frequently prescribed medications for the secondary prevention of cardiovascular and cerebrovascular events. It has recently been reported to cause small intestinal mucosal injury at a considerably higher rate than previously believed. The aim of this study is to investigate the mechanism by which this occurs using an in vitro small intestine model focusing on the role of oxidative stress and cell permeability. Differentiated Caco-2 exhibits a phenotype similar to human small intestinal epithelium. We measured whether ASA induced the increase of differentiated Caco-2 permeability, the decrease of tight junction protein expression, the production of reactive oxygen species (ROS), and the expression of ROS-modified zonula occludens-1 (ZO-1) protein. In some experiments, Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP, a superoxide dismutase mimetic) was used. The nontoxic concentration of ASA decreased transepithelial electrical resistance and increased the flux of fluorescein isothiocyanate-conjugated dextran across Caco-2 in a time-dependent manner. The same concentration of ASA significantly decreased ZO-1 expression among TJ proteins as assessed by Western blot and immunocytochemistry and increased ROS production and the expression of oxidative stress-modified ZO-1 protein. However, MnTMPyP suppressed the ASA-induced increased intercellular permeability and the ASA-induced ROS-modified ZO-1 expression. Our findings indicate that ASA-induced ROS production can specifically modify the expression of ZO-1 protein and induce increased cell permeability, which may ultimately cause small intestinal mucosal injury.

Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency.

BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role in the indomethacin-induced apoptosis in the case of small-intestinal mucosal injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice were included in this study. Mucosal injuries induced by subcutaneously administering indomethacin were evaluated macroscopically, histologically and biochemically. Indomethacin-induced injuries were improved in Bach1-deficient mice. Immunohistochemistry showed an increase in the number of HO-1-positive cells, which were mainly F4/80 positive macrophages, in Bach1-deficient mice. Indomethacin administration increased the expression of HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed mucosal injury, indicating that Bach1 is a novel therapeutic target for indomethacin-induced intestinal injury.

[A case of rectal GIST treated with imatinib mesylate neoadjuvant therapy to preserve the anus].

A 64-year-old man was admitted to our hospital with anal pain on evacuation. MRI revealed a large rectal submucosal tumor, more than 6 cm in diameter. Fine needle histological diagnosis indicated GIST with moderate risk. The patient was treated with imatinib mesylate in order to preserve the anus. The anal pain and tumor size decreased. Trans-anal local excision was performed. This case suggests that imatinib mesylate can make it possible to treat large rectal GIST cases by preserving anus, if neoadjuvant chemotherapy can be effective.