Shinwa Tanaka

Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/Per-ARNT-Sim domain transcription factor, which is activated by various xenobiotic ligands. AHR is known to be abundant in liver tissue and to be associated with hepatic steatosis. However, it has not yet been elucidated how the activation of AHR promotes hepatic steatosis. The aim of this study is to clarify the role of AHR in hepatic steatosis. The intraperitoneal injection of 3-methylcholanthrene (3MC), a potent AHR ligand, into C57BL/6J mice significantly increased the levels of triglycerides and six long-chain monounsaturated fatty acids in the livers of mice, resulting in hepatic microvesicular steatosis. 3MC significantly enhanced the expression level of fatty acid translocase (FAT), a factor regulating the uptake of long-chain fatty acids into hepatocytes, in the liver. In an in vitro experiment using human hepatoma HepG2 cells, 3MC increased the expression level of FAT, and the downregulation of AHR by AHR siRNA led to the suppression of 3MC-induced FAT expression. In addition, the mRNA level of peroxisome proliferator-activated receptor (PPAR) α, an upstream factor of FAT, was increased in the livers of 3MC-treated mice. Taking together, AHR activation induces hepatic microvesicular steatosis by increasing the expression level of FAT.

Endoscopic submucosal dissection of cecal lesions in proximity to the appendiceal orifice

BACKGROUND AND STUDY AIMS Endoscopic submucosal dissection (ESD) is performed for treatment of various gastrointestinal lesions; however, the cecum in proximity to the appendiceal orifice remains a challenging area. We reviewed our experience with cecal ESD near the appendiceal orifice in order to clarify whether this procedure is a safe and effective therapeutic option. PATIENTS AND METHODS We retrospectively reviewed ESD for lesions within approximately 12 mm of the appendiceal orifice at Kobe University Hospital and an affiliated hospital between January 2003 and December 2014. Lesions were classified as: Type 0, proximity to the appendiceal orifice but does not reach it; Type 1, reaches border of the appendix, but does not enter orifice; Type 2, enters orifice, and transition to normal appendiceal mucosa is discernible on inspection of the appendiceal lumen; and Type 3, enters orifice deeply and tumor edge cannot be observed. ESD was not performed for Type 3 lesions unless appendectomy was performed prior to ESD. RESULTS A total of 76 lesions satisfied the inclusion criteria (47 Type 0 lesions, 20 Type 1, 6 Type 2, and 3 Type 3). En bloc resection was achieved in 72 lesions (94.7 %). Median specimen size was 49 mm (range 15 - 114 mm), and median tumor size was 35.5 mm (10 - 110 mm). One patient experienced postoperative bleeding, which was treated by endoscopic hemostasis. Another patient who experienced intraoperative perforation and was treated by clip closure later developed appendicitis; he underwent emergency ileocecal surgical resection. Another patient experienced postoperative appendicitis and recovered with antibiotic treatment. CONCLUSIONS ESD in close proximity to the appendiceal orifice seems safe and effective.

Efficacy of endoscopic submucosal dissection for residual or recurrent superficial colorectal tumors after endoscopic mucosal resection

Superficial colorectal tumors can be treated effectively by endoscopic submucosal dissection (ESD). Few data are available on using ESD for residual or recurrent tumors after the first endoscopic resection. This study aimed to evaluate the efficacy of ESD for these lesions.

Clinical significance of the muscle-retracting sign during colorectal endoscopic submucosal dissection

Background and study aims: During colorectal endoscopic submucosal dissection (ESD), the feature of a muscle layer being pulled toward a neoplastic tumor is sometimes detected. We call this feature the muscle-retracting sign (MR sign). The aim of this study was to evaluate whether the MR sign is associated with particular types of neoplastic lesions and whether it has any clinical significance for ESD sessions. Patients and methods: A total of 329 patients underwent ESD for 357 colorectal neoplasms. The frequency of positivity for the MR sign was evaluated in different morphologic and histopathologic types of neoplasm. The success rate of complete resection and the incidence of complications were also evaluated according to whether lesions were positive or negative for the MR sign. Results: The rates of positivity for the MR sign in the various lesion types were as follows: laterally spreading tumor – granular nodular mixed type (LST-G-M), 9.6 %; laterally spreading tumor – granular homogeneous type (LST-G-H) and laterally spreading tumor – nongranular type (LST-NG), 0 %; sessile type, 41.2 %. The resection rate was 100 % (329 /329) in lesions negative for the MR sign; however, it was 64.3 % (18 /28) in lesions positive for the MR sign, which was significantly lower (P < 0.001). Conclusions: The MR sign was present only in some protruding lesions, and more importantly, it was associated with a high risk of incomplete tumor removal by ESD. Our data indicate that lesions positive for the MR sign lesions should be dissected with great caution; alternatively, based on the features of the individual case, a switch to surgery should be considered for the benefit of the patient.

Risk of stricture after endoscopic submucosal dissection for large rectal neoplasms.

BACKGROUND AND STUDY AIMS Improvements in the endoscopic submucosal dissection (ESD) technique have made circumferential ESD in the rectum possible. However, little is known about the clinical course after extensive ESD in the rectum. The aim of this study was to determine the stricture risk in the rectum after total or subtotal circumferential ESD. PATIENTS AND METHODS A total of 69 patients with 69 rectal tumors that required ≥ 75 % circumferential resection were identified at Kobe University Hospital and an affiliated hospital between April 2005 and May 2014. Among the patients, 61 were available for evaluation of stricture development, either by follow-up colonoscopy or by surgical specimens. The rate and possible risk factors of post-ESD strictures were investigated. RESULTS Post-ESD rectal strictures developed in 12 patients (19.7 %). Patients who underwent total circumferential ESD developed a stricture (5/7, 71.4 %) more frequently than those with subtotal (≥ 90 %) ESD (7/16, 43.8 %). Patients undergoing an ESD procedure that involved < 90 % of the circumference did not develop strictures. The strictures were membranous or < 10 mm long in all cases. Of the patients with stricture, 11 received endoscopic balloon dilation and one received bougie with short-caliber-tip transparent hood; all strictures improved following dilation therapy. Statistical analysis revealed that ≥ 90 % circumferential resection was an independent risk factor for stricture, whereas morphology and size were not. CONCLUSIONS Patients who underwent total or subtotal circumferential ESD of a rectal tumor had a high risk of stricture formation. Dilation helped to alleviate the stenosis.Study registered at University Hospital Medical Information Network (UMIN 000016559).

CLINICOPATHOLOGICAL CHARACTERISTICS OF ABNORMAL MICRO‐LESIONS AT THE ORO‐HYPOPHARYNX DETECTED BY A MAGNIFYING NARROW BAND IMAGING SYSTEM

Background:  Narrow band imaging (NBI) with magnifying endoscopy (NBI‐ME) allows the detection of abnormal micro‐lesions smaller than 5 mm in diameter in the oro‐hypopharynx that could not be visualized previously. The purpose of the present study was to clarify the clinicopathological characteristics of abnormal micro‐lesions of the oro‐hypopharynx detected by NBI‐ME

Inhibitory effects of vitamin K3 derivatives on DNA polymerase and inflammatory activity

Previously, we reported that vitamin K₃ (menadione, 2-methyl-1,4-naphthoquinone) (compound 2) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects (IEs) of vitamin K3 and its derivatives, such as 1,4-naphthoquinone (compound 1) and 1,2-dimethyl-1,4-naphthoquinone (compound 3), on the activity of mammalian pols. Among compounds 1-3 (10 µM for each), compound 1 was the strongest inhibitor of mammalian pols α and λ, which belong to the B and X pol families, respectively, whereas compound 2 was the strongest inhibitor of human pol γ, a family A pol. However, these compounds did not affect the activity of human pol κ, a family Y pol. As we previously found a positive relationship between pol λ inhibition and anti-inflammatory action, we examined whether these vitamin K₃ derivatives are able to inhibit inflammatory responses. Among the three compounds tested, compound 1 caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. In addition, in a cell culture system using RAW264.7 mouse macrophages, compound 1 displayed the strongest suppression of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-evoked acute inflammation, the intraperitoneal injection of compound 1 into mice suppressed TNF-α production in their peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), the vitamin K₃ derivatives markedly suppressed DSS-evoked colitis. In conclusion, this study has identified several vitamin K₃ derivatives, such as compound 1, that are promising anti-inflammatory candidates.

Feasibility and safety of endoscopic submucosal dissection for large colorectal tumors.

Purpose: Recently, endoscopic submucosal dissection (ESD) has been applied for superficial colorectal neoplasms and the number of publications about it has been increasing, but little is known about the outcomes of colorectal ESD for the lesions >50 mm. In this study, we evaluated the feasibility and safety of colorectal ESD for the lesions >50 mm compared with the lesions <50 mm. Methods: A total of 674 superficial colorectal neoplasms in 629 patients treated by ESD at Kobe University Hospital from July 2008 to July 2013 were included in the analysis. Results: The median operation time (range) in the large lesion group (≥5 cm) was 109 (37 to 596) minutes, and it was 55 (6 to 248) minutes in the small lesion group (<5 cm). Median procedure speed (range) in the large lesion group was 0.28 (0.06 to 0.83) cm2/min, and it was 0.19 (0.04 to 0.83) cm2/min in the small lesion group. The en bloc resection rate and the curative resection rate in the small lesion group was 98.7% and 96.0%, and those were 95.7% and 91.4% in the large lesion group, respectively. In terms of adverse events, perforation, muscle damage, and postoperative bleeding occurred at similar frequency in both groups. Conclusions: ESD on colorectal lesions >50 mm takes longer operation time; however, it is resected time effectively without increasing the risk of adverse events compared with smaller lesions by ESD.

Endoscopic vessel sealing: A novel endoscopic precoagulation technique for blood vessels during endoscopic submucosal dissection

1 Kahaleh M, Hernandez AJ, Tokar J, Adams RB, Shami VM, Yeaton P. Interventional EUS-guided cholangiography: Evaluation of a technique in evolution. Gastrointest. Endosc. 2006; 64: 52–9. 2 Park do H, Koo JE, Oh J et al. EUS-guided biliary drainage with one-step placement of a fully covered metal stent for malignant biliary obstruction: A prospective feasibility study. Am. J. Gastroenterol. 2009; 104: 2168–74. 3 Isayama H, Komatsu Y, Tsujino T et al. A prospective randomised study of ‘covered’ versus ‘uncovered’ diamond stents for the management of distal malignant biliary obstruction. Gut 2004; 53: 729–34. 4 Kawakubo K, Isayama H, Nakai Y et al. Simultaneous duodenal metal stent placement and EUS-guided choledochoduodenostomy for unresectable pancreatic cancer. Gut Liver 2012; 6: 399–402.

Feasibility and safety of endoscopic submucosal dissection for lesions involving the ileocecal valve

BACKGROUND AND STUDY AIM Endoscopic submucosal dissection (ESD) has been applied to treat early colorectal cancers. The aim of this study was to clarify the clinical course of ESD for lesions involving the ileocecal valve (ICV) by evaluating the successful resection rates, and the risk and frequency of adverse events. PATIENTS AND METHODS The outcome of ESD on 38 ICV lesions was compared with the outcome of 132 cecal lesions that did not involve the ICV or appendiceal orifice during the same study period. The factors related to longer procedure time, postoperative stricture development, and tumor recurrence were investigated for ESD of ICV lesions. RESULTS There was no significant difference between the ICV and non-ICV groups in the en block resection rates. The median procedure time was significantly longer in the ICV group than in the non-ICV group, with a point estimate of the difference of 37 minutes (95 % confidence interval [CI] 20.00 to 56.00; P  < 0.01). None of the patients developed symptomatic post-ESD stricture or tumor recurrence. ESD procedure duration was ≥ 120 minutes in 16 lesions and < 120 minutes in 22 lesions of the ICV group. A specimen diameter of ≥ 40 mm and tumor extension into terminal ileum were factors related to a longer procedure time (odds ratio [OR] 8.40, 95 %CI 1.53 to 46.10, P = 0.01; OR 10.60, 95 %CI 2.17 to 51.40, P  < 0.01, respectively). CONCLUSIONS ICV lesions can be resected by ESD without major adverse events or causing symptomatic stricture development. However, ESD for ICV lesions should be performed only by expert endoscopists, as the procedure requires accomplished endoscopic skill and experience.