Eisuke Kaji

DNA methylation of colon mucosa in ulcerative colitis patients: Correlation with inflammatory status

Background: Although DNA methylation of colonic mucosa in ulcerative colitis (UC) has been suggested, the majority of published reports indicate the correlation between methylation of colon mucosa and occurrence of UC‐related dysplasia or cancer without considering the mucosal inflammatory status. The aim of this study was to verify whether mucosal inflammation‐specific DNA methylation occurs in the colon of UC. Methods: Of 15 gene loci initially screened, six loci (ABCB1, CDH1, ESR1, GDNF, HPP1, and MYOD1) methylated in colon mucosa of UC were analyzed according to inflammatory status using samples from 28 surgically resected UC patients. Results: Four of six regions (CDH1, GDNF, HPP1, and MYOD1) were more highly methylated in the active inflamed mucosa than in the quiescent mucosa in each UC patient (P = 0.003, 0.0002, 0.02, and 0.048, respectively). In addition, when the methylation status of all samples taken from examined patients was stratified according to inflammatory status, methylation of CDH1 and GDNF loci was significantly higher in active inflamed mucosa than in quiescent mucosa (P = 0.045 and 0.002, respectively). Multiple linear regression analysis revealed that active inflammation was an independent factor of methylation for CDH1 and GDNF. DNA methyltransferase 1 and 3b were highly expressed in colon epithelial cells with active mucosal inflammation, suggesting their involvement in inflammation‐dependent methylation. Conclusions: Methylation in colonic mucosa of UC was correlated with mucosal inflammatory status, suggesting the involvement of methylation due to chronic active inflammation in UC carcinogenesis. (Inflamm Bowel Dis 2011;)

ADVANTAGES OF USING THIN ENDOSCOPE‐ASSISTED ENDOSCOPIC SUBMUCOSAL DISSECTION TECHNIQUE FOR LARGE COLORECTAL TUMORS

Background:  Our purpose was to evaluate the effectiveness of a newly developed non‐invasive traction technique known as thin endoscope‐assisted endoscopic submucosal dissection (TEA‐ESD) procedure for the removal of colorectal laterally spreading tumors (LST).

EMR of mucosa-associated lymphoid tissue lymphoma of the rectum

There are numerous reports of mucosa-associated lymphoid tissue (MALT) lymphoma involving the large intestine. Several studies have reported that anti-Helicobacter pylori treatment induced regression of colorectal MALT lymphoma, regardless of the presence or absence of H pylori.1-4 Here, a case is reported of rectal MALT lymphoma (negative for H pylori) diagnosed 7 years after surgical resection of MALT lymphoma of the sigmoid colon. The new lesion was treated by EMR.

Analysis of K-ras, BRAF, and PIK3CA mutations in laterally-spreading tumors of the colorectum.

Background and Aims:  Laterally‐spreading tumors (LST) are a newly‐recognized category of colorectal neoplasia, and are defined as lesions larger than 10 mm in diameter and extending circumferentially rather than vertically. However, genetic features of this new category of tumors are not fully elucidated. The aim of this study was to evaluate genetic alterations in LST.

A target-controlled infusion system with bispectral index monitoring of propofol sedation during endoscopic submucosal dissection

Background and study aims: Propofol administration via a target-controlled infusion system with bispectral index monitoring (BIS/TCI system) is expected to prevent complications from sedation during complex and long endoscopic procedures. We evaluated the feasibility of setting the BIS/TCI system for non-anesthesiologist administration of propofol (NAAP) during endoscopic submucosal dissection (ESD). Patients and methods: From May 2009 to February 2013, 250 patients with esophagogastric neoplasms were treated with ESD using the BIS/TCI system with NAAP. In the TCI system, the initial target blood concentration of propofol was set at 1.2 μg/mL. The titration speed of propofol was adjusted according to the BIS score and the movement of the patient. The BIS target level ranged from moderate to deep sedation, at which a stable BIS score between 60 and 80 was obtained. Results: In 80.4 % of patients, it was possible to maintain stable sedation with a blood concentration of propofol of less than 1.6 µg/mL using TCI throughout the ESD procedure. The default setting for ideal blood concentration of propofol was 1.2 μg/mL, because the medians of the lower and upper bounds of blood concentration were 1.2 μg/mL (range 0.6 – 1.8 μg/mL) and 1.4 μg/mL (range 1.0 – 3.8 μg/mL), respectively. Although hypotension occurred in 27 patients (10.8 %), oxygen desaturation occurred in only nine patients (3.6 %), and severe desaturation in only two patients (0.8 %). Conclusions: Using our settings, it is possible for a non-anesthesiologist to maintain stable sedation during a lengthy endoscopic procedure through propofol sedation with a BIS/TCI system.

Methylation of estrogen receptor 1 in colorectal adenomas is not age-dependent, but is correlated with K-ras mutation

The promoter region of estrogen receptor 1 (ESR1) has been shown to be methylated in normal colorectal mucosa in an age‐dependent manner. However, the methylation of this region in colorectal tumors has not sufficiently been investigated. The methylation status of ESR1 in 105 colorectal adenoma tissues was examined by MethyLight and presented as the percentage of methylated references (PMR). Factors that affect the PMR of ESR1 in adenomas were determined using parameters including patient age, sex, past history of malignancy, family history of colorectal cancer, smoking and drinking habits, clinical characteristics of adenomas (location, size, macroscopic appearance, and histology), and K‐ras mutation. Multiple linear regression revealed that the PMR was not correlated with patient age. K‐ras mutation was significantly correlated with the higher methylation status of ESR1 in adenoma (t‐value = 3.21, P = 0.0018), whereas alcohol exposure was significantly correlated with lower methylation status (t‐value = –2.37, P = 0.02). Because methylation of O6‐methylguanine DNA methyltransferase (MGMT) has been reported to be correlated with K‐ras G‐to‐A transition, methylation of ESR1 was compared with that of MGMT with regard to K‐ras mutation. Contrary to expectations, methylation of MGMT was not significantly correlated with K‐ras G‐to‐A transition, but that of ESR1 was strongly correlated with K‐ras G‐to‐A transition. Thus, the methylation status of ESR1 in adenomas was not correlated with patient age, but was associated with K‐ras mutation, suggesting that methylation of ESR1 in tumors functions differently from that in normal colon mucosa. (Cancer Sci 2009; 100: 1005–1011)

Tu1228 Disparity in Clinical Care for Patients With Inflammatory Bowel Disease Between Specialists and Non-Specialists

Background: Although inflammatory bowel disease (IBD) patients have been increasing and new therapeutic options for IBD have been developed, there are relatively few clinicians who specialize in IBD. Patients treated by a non-specialist of IBD may not receive appropriate treatment. This study aimed to compare disease and medication status between IBD patients treated by a specialist and those treated by a non-specialist. Methods: Medical charts of ambulating IBD patients in two hospitals were examined. All patients in one hospital were treated by one of the IBD specialists, while in the other hospital, patients were treated by one of the gastroenterologists who was a non-specialist of IBD. Results: The numbers of IBD patients were 255 (hospital with specialists) and 74 (hospital without specialists), respectively. Disease activity of the patients was not well-controlled in the hospital without specialists compared to in the hospital with specialists (ulcerative colitis (UC): p = 0.0006 and Crohn’s disease: p = 0.012, respectively). The proportion of UC patients who received an insufficient dose of mesalazine (Pentasa < 3 g/day or Asacol < 3.6 g/day) was higher in the hospital without specialists (47% vs. 15%, p < 0.0001). In the hospital without specialists, more patients received long-term corticosteroids (UC: 23% vs. 5%, p < 0.0001), while fewer patients received immunomodulators (UC: 8% vs. 46%, p < 0.0001). Conclusions: IBD patients of the hospital without specialists were not well-controlled and were not prescribed appropriately with therapeutic drugs. Fostering and placement of the specialist of IBD is an urgent problem.

Serum folate and homocysteine levels are associated with colon tumorigenesis in end-stage renal disease patients

The aim of this study was to evaluate the effect of folate and homocysteine on colon tumorigenesis by performing colonoscopy and examining serum folate and homocysteine levels in end-stage renal disease (ESRD) patients. We performed colonoscopy in 72 ESRD patients who were undergoing hemodialysis and also measured their serum folate and homocysteine levels. Serum folate and homocysteine concentrations of the 72 ESRD patients were 6.0 ± 3.9 μg/l and 37.3 ± 25.5 μmol/l, respectively. Colorectal neoplasia was detected in 47 (65%) of the patients. Compared to a control group, ESRD patients had significantly more and larger neoplasia (P = 0.002 and 0.001, respectively). Multivariate analysis revealed that ESRD patients with lower levels of serum homocysteine had significantly more and larger neoplasia than those with higher levels (P = 0.02 and 0.03, respectively). In addition, patients with a shorter duration of hemodialysis were likely to have larger neoplasia. ESRD patients had higher than normal serum homocysteine levels. Interestingly, patients with lower homocysteine levels were likely to carry more and larger colorectal neoplasia. These results suggest that suppression of folate metabolism and an elevated serum homocysteine concentration are inversely associated with colon tumorigenesis in ESRD patients.

Mo1673 Evaluation of Mucosal Healing of Ulcerative Colitis by Using a Quantitative Fecal Immunochemical Test

Background and Aim: Evidence has been accumulated to show that achievement of mucosal healing (MH) is associated with sustained clinical remission, and reduced rates of hospitalization and surgical resection. The combination of oral and topical mesalazine is thought to be more effective than alone in patients with mild-to-moderate disatal colitis and mild-tomoderate extensive colitis. However, endoscopic evaluation of the combined treatment on colonic mucosa is scarce. We conducted conventional endoscopic evaluation as well as segmental endoscopic evaluation in mild-to-moderate ulcerative colitis (UC) patients treated with oral Pentasa® and Pentasa® enema. Materials and Methods: Patients with active mildto-moderate UC were included and treated with 4 g/day of mesalazine combined with 1 g/ day mesalazine enema for 8 wks. At both baseline and 8 wks patients were endoscopically asseseed using Mayo Endoscopic Score and using Segmental Endoscopic Score. Segmental endoscopic evaluation was performed for each of 8 contiguous anatomic segments (rectum below/above the peritoneal reflection, rectosigmoid, sigmoid, left colon, transverse, right colon, cecum). The criteria of segmental endoscopy included erythema, vascular pattern, friability and erosion/ulcer (score range per segment: 0 10). MH was defined as Mayo Endoscopic Score = 0, 1. Disease activity was also assessed at baseline and 8 wks using the UC Disease Activity Index (UCDAI), with clinical and endoscopic signs. Remission and improvement were defined as a UCDAI score < 2 and as a decrease of UCDAI score by ≥ 2 points from baseline, respectively. Abbreviated UCDAI score (aUCDAI) obtained from stool frequency, rectal bleeding and physicians global assessment was assessed at baseline, 4 and 8 wks. Result: Of the 31 patients included, 29 completed endoscopic evaluations at both baseline and 8 wks. Median disease duration was 72.7 months and mean baseline UCDAI score was 6.72. The extents of disease were 10.3% in proctitis, 34.5% in left-sided colitis and 55.2% in extensive colitis. Mayo endscopic score significantly decreased from 2.14 to 1.45 (p < 0.001) and MH rate was 51.7%. The segmental endscopic scores of every assessed area at 8 wks decreased significantly compared to that at baseline (Table). UCDAI significantly decreased from 6.72 to 3.00 (p < 0.001). Remission and improvement rates were 31.0% and 79.3%, respectively. aUCDAI significantly decreased from 4.59 at baseline to 1.76 at 4 wks and 1.55 at 8 wks (p < 0.001). Conclusion: These results demonstrate that the combination of oral and topical mesalazine ameliorates mucosal appearances of the whole colon with fast clinical improvement. Therefore, combined mesalazine therapy is thought to be the optimum first line therapy for mild-to-moderate UC patients independent of the extent of disease. Segmental Endoscopic Score

Do Smoking and Drinking Habits and Obesity Affect Prevalence of Colorectal Neoplasia in Patients With Positive Immunochemical Fecal Occult Blood Test

G A A b st ra ct s tertiary center. Prolonged SBTT was defined as >6 hours. Regional and whole gut transit times were analyzed. For pts with slow SBTT, average amplitude (AUC) and frequency of contractions (Ct) 60 minutes before and after gastric emptying (GET) were analyzed and compared to the pressure profile of 66 healthy controls. Results: 77 pts underwent WMC test due to upper GI symptoms and suspected GI dysmotility. Of those, 10 pts (13%) had SB motility disorder with isolated prolonged SBTT, but normal gastric and colon transit times. Mean SBTT was 461 min (360-600), significantly longer than normal (p=0.001). The CTT in this group was not significantly different from healthy subjects. There was a tendency to have longer, although normal, mean GET 239 min (p=0.04), compared to healthy subjects. Pressure data: no significant differences were found between pts with isolated slow SBTT and healthy controls in Ct and AUC. The clinical presentation of the pts with isolated SBTT delay was analyzed. Upper GI symptoms were the most common: upper abdominal pain and discomfort -80%, bloating60%, nausea-50%, early satiation-50%, fullness sensation40%, vomiting30%, weight loss30%, abdominal distention-30%, loss of appetite20%, constipation50%. Two pts had DM. In all pts, extensive GI work up, including GES in 2 pts, was unrevealing prior to the WMC test. Following documenting of slow SBTT, in 50% of pts new treatment was initiated -3 pts were treated with lubiprostone, 2 pts were treated for SIBO. Conclusions: SB transit delay might be the underlining pathophysiology for GI symptoms in a subset of pts. Postprandial symptoms are the most common. Evaluation of SBTT by WMC might be considered for patients with upper GI symptoms resembling gastroparesis, in whom no other abnormality of GI tract was identified. An abnormal SBTT could serve as a target for treatment if found.