Extensive and systematic rewiring of histone post-translational modifications in cancer model systems.

Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short-term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations.

Microsatellite instability test using peptide nucleic acid probe-mediated melting point analysis: a comparison study.

BACKGROUND: Analysis of high microsatellite instability (MSI-H) phenotype in colorectal carcinoma (CRC) is important for evaluating prognosis and choosing a proper adjuvant therapy. Although the conventional MSI analysis methods such as polymerase chain reaction (PCR) fragment analysis and immunohistochemistry (IHC) show high specificity and sensitivity, there are substantial barriers to their use. METHODS: In this study, we analyzed the MSI detection performance of three molecular tests and IHC. For the molecular tests, we included a recently developed peptide nucleic acid probe (PNA)-mediated real-time PCR-based method using five quasi-monomorphic mononucleotide repeat markers (PNA method) and two conventional PCR fragment analysis methods using NCI markers (NCI method) or five quasi-monomorphic mononucleotide repeat markers (MNR method). IHC analysis was performed with four mismatch repair proteins. The performance of each method was validated in 166 CRC patient samples, which consisted of 76 MSI-H and 90 microsatellite stable (MSS) CRCs previously diagnosed by NCI method. RESULTS: Of the 166 CRCs, 76 MSI-H and 90 MSS CRCs were determined by PNA method. On the other hand, 75 MSI-H and 91 MSS CRCs were commonly determined by IHC and MNR methods. Based on the originally diagnosed MSI status, PNA showed 100% sensitivity and 100% specificity while IHC and MNR showed 98.68% sensitivity and 100% specificity. When we analyzed the maximum sensitivity of MNR and PNA method, which used the same five markers, PNA method could detect alterations in all five mononucleotide repeat markers in samples containing down to 5% MSI-H DNAs, whereas MNR required at least 20% MSI-H DNAs to achieve the same performance. CONCLUSIONS: Based on these findings, we suggest that PNA method can be used as a practical laboratory test for the diagnosis of MSI.

Postoperative adjuvant chemotherapy is associated with a lower incidence of colorectal adenomas in patients with previous colorectal cancer.

BACKGROUND AND AIMS: The effects of chemotherapeutic agents on the development of colorectal adenomas in patients with previous colorectal cancer (CRC) are not defined. Therefore, we evaluated the potential effect of adjuvant chemotherapy on the incidence of colorectal adenomas in patients with previous CRC. METHODS: We selected patients with low-risk stage II CRC with or without postoperative 5-fluorouracil-based adjuvant chemotherapy to reduce selection bias. Among 1808 patients with stage II CRC who underwent colonoscopic surveillance after curative resection of CRC between 2006 and 2013, 192 patients were retrospectively enrolled in this study after matching for age and sex. The patients were divided into 96 patients receiving and 96 patients not receiving 5-fluorouracil-based chemotherapy. RESULTS: Forty patients (41.7%) exhibited colorectal adenomas among 96 patients who received adjuvant chemotherapy, compared with 50 patients (52.1%) with colorectal adenomas among 96 patients who received surgery only. The incidence rate of advanced adenoma was significantly lower in the chemotherapy group than in the nonchemotherapy group (3.1% vs 10.4%, P = .044). After adjustment for clinically relevant factors such as body mass index, aspirin use, metformin use, number of follow-up colonoscopies, and operation type, adjuvant chemotherapy was found to be associated with a decreased incidence of advanced adenoma (odds ratio, .151; 95% confidence interval, .035-.653; P = .011) in patients with stage II CRC. CONCLUSIONS: The results showed that chemotherapy in patients with CRC may be associated with a lower risk of colorectal advanced adenoma development.

Clinical Outcomes of Self-Expandable Metal Stents for Malignant Rectal Obstruction.

BACKGROUND: Self-expandable metal stents are widely used to treat malignant colorectal obstruction. However, data on clinical outcomes of stent placement for rectal obstruction specifically are lacking. OBJECTIVE: We aimed to investigate the clinical outcomes of self-expandable metal stents in malignant rectal obstruction in comparison with those in left colonic obstruction and to identify factors associated with clinical failure and complication. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Between January 2005 and December 2013, medical charts of patients who underwent stent placement for malignant rectal or left colonic obstruction were reviewed retrospectively. INTERVENTION: Study intervention included self-expandable metal stent placement. MAIN OUTCOME MEASURES: Technical success, clinical success, and complications were measured. RESULTS: Technical success rates for the 2 study groups (rectum vs left colon, 93.5% vs 93.1%; p = 0.86) did not differ significantly; however, the clinical success rate was lower in patients with rectal obstruction (85.4% vs 92.1%; p = 0.02). In addition, the complication rate was higher in patients with rectal obstruction (37.4% vs 25.1%; p = 0.01). Patients with rectal obstruction showed higher rates of obstruction because of extracolonic malignancy (33.8% vs 15.8%; p < 0.001) and stent use for palliation (78.6% vs 56.3%; p < 0.001). Multivariate analysis indicated obstruction attributed to extracolonic malignancy and covered stent usage to be independent risk factors for clinical failure. Factors predictive of complications in the palliative group were total obstruction, obstruction because of extracolonic malignancy, and covered stent usage. LIMITATIONS: This was a retrospective, single-center study. CONCLUSIONS: The efficacy and safety of stent placement for malignant rectal obstruction were comparable with those for left colonic obstruction. However, obstruction attributed to extracolonic malignancy, use of covered stents, and total obstruction negatively impacted clinical outcomes of self-expandable metal stent placement and must be considered by endoscopists. See Video Abstract at http://links.lww.com/DCR/A417.

The role of endoscopic evaluation for radiation proctitis in patients receiving intermediate-dose postoperative radiotherapy for rectal cancer.

OBJECTIVES: High-dose pelvic radiotherapy (RT) is known to be associated with chronic radiation proctitis (RP). However, the effects of intermediate radiation doses are unknown. We assessed the incidence of late clinical RP among patients with rectal cancer receiving intermediate-dose postoperative RT, as well as the role of early endoscopic abnormalities in predicting RP development. METHODS: We retrospectively reviewed 153 patients with rectal cancer who received postoperative RT at a median dose of 54 Gy between 2005 and 2009 and who underwent endoscopic examination within 12 months thereafter. Endoscopic RP was assessed using the Vienna rectoscopy score (VRS). Late clinical RP toxicity was evaluated, as was its correlation with endoscopic RP. RESULTS: All patients underwent an endoscopic examination at a median of 9 months after postoperative pelvic RT. Endoscopic RP was detected in 45 patients (29.4%); the predominant patterns were telangiectasia and congested mucosa. During the median 88-month follow-up period, 29 patients (19.0%) experienced late clinical RP; only 3 (2.0%) had Grade 3 or above. The VRS predicted the development of late clinical RP as well as its cumulative incidence (P < 0.001). Endoscopic evidence of telangiectasia was significantly associated with the development of late clinical RP (P < 0.001). CONCLUSIONS: Early endoscopic findings using VRS are useful for predicting the possibility of late clinical RP, although the incidences of severe cases were low. Patients with endoscopic abnormalities should be followed closely owing to their susceptibility to clinical RP.

The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma.

PURPOSE: Existing studies suggest that metformin lowers the risk and mortality of colorectal cancer. However, the effect of metformin on the suppression and prevention of colorectal adenomas is not clear. The aim of this study was to evaluate the effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. METHODS: Among 423 diabetic patients who underwent surveillance colonoscopy after resection of colorectal adenoma between 2005 and 2011, 257 patients were retrospectively reviewed. The patients were divided into two groups: one group comprising 106 patients who took metformin and another group comprising 151 patients who did not take metformin. The clinical characteristics, colorectal adenoma recurrence, and valuable factors for adenoma recurrence were analyzed. RESULTS: At surveillance colonoscopy after colonoscopic polypectomy for adenoma, 38 patients (35.8%) exhibited colorectal adenoma among 106 patients who took metformin, compared with 85 patients (56.3%) with colorectal adenoma among 151 patients who did not take metformin (odds ratio 0.434, 95% confidence interval 0.260-0.723, P = 0.001). Multivariate Cox analysis showed that metformin was associated with decreased recurrence of colorectal adenoma (hazard ratio 0.572, 95% confidence interval 0.385-0.852, P = 0.006) in diabetic patients with previous colorectal adenoma. The cumulative probability of colorectal adenoma recurrence was significantly lower in the metformin group than in the non-metformin group (P = 0.001). CONCLUSION: Metformin use in diabetic patients with previous colorectal adenoma is associated with a lower risk of colorectal adenoma recurrence.

Risk factors and outcomes of acute lower gastrointestinal bleeding in intestinal Behçet's disease.

BACKGROUND: Intestinal Behçet's disease (BD) can cause acute lower gastrointestinal bleeding, which is sometimes fatal. AIM: We aimed to identify the risk factors and outcomes of acute lower gastrointestinal bleeding and factors associated with rebleeding in intestinal BD patients. METHODS: Of the total of 588 intestinal BD patients, we retrospectively reviewed the medical records of 66 (11.2%) patients with acute lower gastrointestinal bleeding and compared them with those of 132 matched patients without bleeding. RESULTS: The baseline characteristics were comparable between the bleeding group (n = 66) and the non-bleeding group (n = 132). On multivariate analysis, the independent factors significantly associated with lower gastrointestinal bleeding were older age (>52 years) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.058-4.684, p = 0.035) and a nodular ulcer margin (HR 7.1, 95% CI 2.084-24.189, p = 0.002). Rebleeding occurred in 23 patients (34.8%). Female patients (p = 0.044) and those with previous use of corticosteroids or azathioprine (p = 0.034) were more likely to develop rebleeding. On multivariate analysis, only use of steroids or azathioprine was significantly associated with rebleeding (HR 3.2, 95% CI 1.070-9.462, p = 0.037). CONCLUSIONS: Age >52 years and the presence of a nodular margin of the ulcer were found to be related to increased risk of bleeding in patients with intestinal BD. Rebleeding is not uncommon and not effectively prevented with currently available medications. Further studies are warranted to identify effective measures to decrease rebleeding in intestinal BD.

Fecal calprotectin as a non-invasive biomarker for intestinal involvement of Behçet's disease.

BACKGROUND AND AIM: The diagnostic and prognostic values of fecal calprotectin (FC) levels in patients with inflammatory bowel diseases have been proven. However, little is known about the usefulness of FC measurement in predicting intestinal involvement of Behçet's disease (BD). METHODS: Forty-four consecutive patients with systemic BD who underwent colonoscopy for the evaluation of gastrointestinal symptoms were prospectively enrolled between November 2012 and March 2014 in a single tertiary medical center. Fecal specimens from the patients were obtained the day before bowel cleansing and 3 months after colonoscopy. RESULTS: Twenty-five patients showed intestinal ulcerations on colonoscopy (12 [48.0%] typical and 13 [52.0%] atypical ulcerations). The median FC level in the intestinal BD group was significantly higher than that in the non-diagnostic group (112.53 [6.86-1604.39] vs 31.64 [5.46-347.60] µg/g, respectively, P = 0.003). Moreover, the typical ulceration group showed a significantly higher median FC level than the atypical ulceration group in patients with intestinal BD (435.995 [75.65-1604.39] vs 71.42 [6.86-476.94] µg/g, respectively, P = 0.033). Multivariate analysis revealed higher FC as an independent predictor of intestinal BD (OR = 38.776; 95% CI = 2.306-652.021; P = 0.011). The cut-off level of FC for predicting intestinal BD was 68.89 µg/g (76% sensitivity and 79% specificity). The absolute changes between fecal calprotectin levels and the disease activity index of intestinal BD from initial diagnosis of intestinal BD to 3 months after diagnosis were significantly correlated (Pearson's correlation coefficient = 0.470, P = 0.027). CONCLUSION: The FC level might serve as a non-invasive surrogate marker of intestinal involvement of BD.

Probe-based confocal laser endomicroscopy for evaluating the submucosal invasion of colorectal neoplasms.

BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) is a novel method for in vivo histological analysis of colorectal neoplasm mucosa, which provides meaningful information for the development of adequate therapeutic strategies. However, the in vivo histology of colorectal neoplasm submucosa has not been studied. We assessed the feasibility and safety of pCLE for evaluating colorectal submucosa, and identified and validated diagnostic criteria for submucosal carcinoma infiltration. METHODS: From March to July 2014, 83 pCLE videos of 51 lesions in 31 patients who underwent scheduled colonoscopic procedures for the removal of colorectal neoplasms were acquired consecutively. During the procedures, pCLE videos of the lesions and biopsy samples for histopathological analysis were acquired. Final histopathological results were used as the gold standard. RESULTS: Based on the confocal pattern, we classified colorectal submucosa findings as negative (superficial submucosa, deep submucosa, and submucosa with fibrosis) or indicative of carcinoma infiltration. Dark and irregular cell nests with irregular cell architecture and little or no mucin were seen in submucosal carcinoma infiltration. Based on rates of correlation with pathological findings, the sensitivity, specificity, and accuracy of the classification of submucosal carcinoma infiltration by two observers were 91.7, 86.8, and 88.0 %, respectively. In addition, the results showed good interobserver agreement for the detection of submucosal carcinoma infiltration (κ = 0.757, standard error = 0.102). No adverse events occurred during the procedures. CONCLUSIONS: Submucosa assessment by pCLE is feasible and safe. pCLE is useful for the differentiation of normal submucosa from carcinoma infiltration, particularly when infiltration is accompanied by severe fibrosis. Large-scale prospective studies are needed to further evaluate the clinical impact of the use of pCLE during endoscopy.

Proteomic Analysis of Serum Amyloid A as a Potential Marker in Intestinal Behçet's Disease.

BACKGROUND/AIMS: Data regarding biomarkers to understand disease pathogenesis and to assess disease activity of intestinal Behçet's disease (BD) are limited. Therefore, we aimed to investigate the differentially expressed proteins in sera from patients with intestinal BD and to search for biomarkers using mass spectrometry-based proteomic analysis. METHODS: Serum samples were pooled for the screening study, and two-dimensional electrophoresis (2-DE) was performed to characterize the proteins present in intestinal BD patients. Candidate protein spots were identified using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and bioinformatic analysis. To validate the proteomic results, serum samples from an independent cohort were assessed by enzyme-linked immunosorbent assay. RESULTS: Pooled serum samples were used for 2-DE, and approximately 400 protein spots were detected in the sera of intestinal BD patients. Of the 22 differentially expressed proteins, 3 were successfully identified using MALDI-TOF/TOF MS. The three up-regulated proteins identified in the intestinal BD group included fibrin, apolipoprotein A-IV, and serum amyloid A (SAA). Serum SAA in intestinal BD patients (2.76 ± 2.50 ng/ml) was significantly higher than that in controls (1.68 ± 0.90 ng/ml, p = 0.007), which is consistent with the proteomic results. In addition, the level of IL-1ß in patients with intestinal BD (8.96 ± 1.23 pg/ml) was higher than that in controls (5.40 ± 0.15 pg/ml, p = 0.009). SAA released by HT-29 cells was markedly increased by tumor necrosis factor-α (TNF-α) and lipopolysaccharides stimulation. CONCLUSIONS: Our proteomic analysis revealed that SAA was up-regulated in intestinal BD patients.

Tumor characteristics associated with malignant large bowel obstruction in stage IV colorectal cancer patients undergoing chemotherapy.

PURPOSE: Little is known about predictable clinical factors associated with the occurrence of malignant large bowel obstruction (MLBO) in incurable stage IV colorectal cancer (CRC) patients undergoing medical treatment. This study investigates the clinical characteristics associated with MLBO that occurred while patients with stage IV CRC were receiving chemotherapy. METHODS: A total of 216 patients who were diagnosed with stage IV CRC without bowel obstruction and who received chemotherapy between May 2005 and June 2012 were retrospectively included in this study. Patients were divided into an "obstruction group" and a "non-obstruction group" based on whether they did or did not develop MLBO during chemotherapy or follow-up, respectively. The initial endoscopic findings and clinical information were retrospectively reviewed and compared between the two groups. RESULTS: Forty-six patients (21.3 %) developed MLBO during the treatment or follow-up periods. The mean duration between diagnosis and MLBO was 9.8 ± 9.3 months. After adjusting for clinically relevant factors, MLBO development was independently associated with the following factors: higher initial tumor-occupying circumference (HR 1.030 [95 % CI, 1.012-1.049], P = 0.001), longer initial horizontal tumor width (HR 1.035 [95 % CI, 1.011-1.059], P = 0.004), primary tumor location at a turning point in the colon (HR 2.404 [95 % CI, 1.185-4.877], P = 0.015), and the presence of primary tumor ulceration at presentation (HR 3.767 [95 % CI, 1.882-7.538], P < 0.001). MLBO development was not associated with tumor response to chemotherapy. CONCLUSION: In patients with stage IV CRC, MLBO development during chemotherapy treatment is associated with tumor ulceration, location, circumference, and width at diagnosis.

Effect of doping level of colored TiO2 nanotube arrays fabricated by electrochemical self-doping on electrochemical properties.

Recently, two types of TiO2 nanotube arrays (NTAs) (blue- and black-colored TiO2 NTAs), which are easily fabricated by electrochemical self-doping, have gained much attention due particularly to their enhanced capacitive and oxidant-generating properties. These enhanced electrochemical properties mean that they have potential as basic materials for energy and environmental applications, such as in supercapacitors and anodes for water treatment. However, the understanding of the effect of the doping level of these TiO2 NTAs on their electrochemical properties is limited because there is no direct comparison or relevant discussion of their respective electrochemical properties under the same conditions, despite the similar surface characteristics of the TiO2 NTAs obtained by comparable electrochemical doping. Therefore, the objective of this study was to investigate the effect of the doping level of blue and black TiO2 NTAs on their electrochemical properties, including the capacitive and oxidant-generating properties. Although no significant difference in their surface properties was found using SEM, XRD and XPS, the black TiO2 NTA revealed a slightly higher doping level than the blue TiO2 NTA, which is caused by the order of the electrochemical self-doping and annealing conditions. With the different doping levels of the two TiO2 NTAs, the black TiO2 NTA showed a higher areal capacitance, indicating good capacitive properties, and better service life in oxidant-generation than that of the blue TiO2 NTA. The blue TiO2 NTA exhibited a larger oxygen evolution overpotential and higher chlorine evolution efficiency than that of the black TiO2 NTA. We report that the new knowledge on blue and black TiO2 NTAs from this study can contribute to the further development of supercapacitors and oxidant-generating anodes for water treatment.

High-risk metachronous polyps are more frequent in patients with traditional serrated adenomas than in patients with conventional adenomas: a multicenter prospective study.

BACKGROUND AND AIMS: Although the malignant progression of serrated polyps has been clearly documented, the malignant potential of the traditional serrated adenoma (TSA) subtype has not been established. We compared the prevalence of metachronous polyps in surveillance colonoscopies between patients with TSA and those with conventional adenomas (CAs). METHODS: Four hundred twenty patients were diagnosed with TSAs by current diagnostic criteria at 10 tertiary care university hospitals in Korea from January 2003 to December 2005; 186 patients who received surveillance colonoscopy after removal of initial polyps were enrolled. During the same time period, 372 age- and sex-matched patients diagnosed with CAs were used as a control group. RESULTS: TSA patients had a significantly higher recurrence rate of colorectal polyps compared with CA patients (66.1% vs 43.5%, respectively). TSA patients had a greater number (3 vs 2) and larger size (8.6 ± 5.7 vs 6.3 ± 5.2 mm) of recurrent polyps compared with CA patients. TSA patients also had a higher rate of CA (54.8% vs 37.9%), serrated adenoma (14.0% vs. 0.8%), and hyperplastic polyp (33.3% vs. 13.7%) recurrence compared with CA patients. TSA patients had significantly greater odds of having a recurrent high-risk polyp than CA patients (odds ratio, 2.37; 95% confidence interval, 1.55-3.63). CONCLUSIONS: In comparison with patients with CAs, patients with TSAs have a higher metachronous occurrence rate of all polyp subtypes including CAs, serrated adenomas, and hyperplastic polyps. Moreover, the presence of TSAs is an independent predictor of a high-risk polyp occurrence.

Factors that affect visibility during endoscopic hemostasis for upper GI bleeding: a prospective study.

BACKGROUND: Adequate visibility is an important factor for achieving successful endoscopic hemostasis for the treatment of upper GI bleeding (UGIB). The independent factors that affect visibility during endoscopic procedures have yet to be determined. OBJECTIVE: To determine the factors that affect endoscopic visibility and to create a model that can predict in which patients unacceptable visibility is suspected before emergent endoscopic procedures for UGIB. DESIGN: Prospective, observational study. SETTING: University-affiliated tertiary care hospital in South Korea. PATIENTS: A total of 121 patients admitted because of UGIB. INTERVENTION: Analysis of the visibility score of the emergency endoscopies for UGIB. MAIN OUTCOME MEASUREMENTS: Factors affecting the visibility score of endoscopy and a classification and regression tree (CART) model for predicting of visibility. RESULTS: The EGD time and the appearance of the nasogastric (NG) tube aspirate were independent factors that were significantly associated with visibility (EGD time, P<.001; red blood appearance in NG tube aspirate, P<.001; coffee grounds appearance of NG tube aspirate, P=.006). Based on these results, a CART model was developed by using 70 patients who had been allocated to the training set. The CART generated algorithms that proposed the use of the appearance of the NG tube aspirate and the EGD time (8.5 hours) to predict visibility. The sensitivity and specificity for predicting poor visibility were 71.4% and 86.4%, respectively. CONCLUSION: The use of the CART model enables the prediction of which patients will have poor visibility during emergent endoscopy.

What is the necessity of endoscopist for successful endoscopic stenting in patients with malignant colorectal obstruction?

BACKGROUND AND AIM: Recently, self-expandable metal stents (SEMSs) have been widely used as an initial therapy for relieving malignant colorectal obstructions. However, several factors, including the endoscopist's experience, affect the clinical outcome of SEMSs. The aim of this study was to define the adequate level of experience necessary to perform endoscopic stenting effectively and safely and to identify technical factors for successful stenting. METHODS: Between March 2009 and June 2012, 160 patients underwent SEMS placement for malignant colorectal obstruction with the intent of palliation or as a bridge to surgery by a single endoscopist who experienced colonoscopy and endoscopic retrograde cholangiopancreatography. RESULTS: The overall technical and clinical success rates were 86.9 and 86.4%, respectively, and 18 complications (11.3%) were observed. There were no differences in any of the clinical outcomes between the consecutive blocks; however, the procedure time decreased significantly after the first 30 procedures (17.4, 16.9, 13.5, and 12.8 min; P = 0.044). American Society of Anesthesiologists (ASA) class, history of a previous operation, proximal colon obstruction, obstruction caused by an extracolonic malignancy, and palliative SEMS placement were associated with technical failure. CONCLUSIONS: An endoscopist who experiences a colonoscopy and fluoroscopy performs SEMS placement successfully regardless of the level of experience. After the first 30 procedures, a SEMS insertion could be safely and effectively performed with short procedure time in patients with malignant colorectal obstruction.

Comparison of clipping with and without epinephrine injection for the prevention of post-polypectomy bleeding in pedunculated colon polyps.

BACKGROUND AND AIM: Post-polypectomy bleeding (PPB) is the most common adverse event of colonoscopic polypectomy, especially in cases with large pedunculated polyps. To minimize the risk of PPB, several endoscopic preventive methods have been performed. The aim of this prospective, randomized study was to compare the rates of PPB following single (clipping alone) and combined (clipping plus epinephrine-saline injection) methods in prevention of PPB in large pedunculated polyps. METHODS: Adult patients with pedunculated colorectal polyps with heads ≥ 10 mm were prospectively enrolled from March 2011 to January 2013. Patients were randomized to receive treatment of either clips alone (group A) or clips plus injection of epinephrine-saline (group B) prior to a conventional polypectomy. PPB rate in both groups were compared. RESULTS: A total of 148 patients with 173 pedunculated colorectal polyps were enrolled. Groups A and B each had 74 patients, with 83 and 90 polyps, respectively. The mean head diameters were 17.2 ± 6.6 and 17.5 ± 6.7 mm in groups A and B, respectively (P = 0.748). Immediate PPB (IPPB) occurred in 10 cases (12.0%) from group A and 13 cases (14.4%) from group B (P = 0.64). There were no cases of delayed PPB or perforation. Multivariate analysis showed that inadequate bowel preparation and large head diameter of polyp were independent risk factors for IPPB. CONCLUSIONS: The rate of IPPB is relatively high in cases with large pedunculated polyps, but these polyps can be successfully resected by snare polypectomy following use of the single prophylactic clipping method.

Seasonal Variation in Flares of Intestinal Behçet's Disease.

BACKGROUND: There have been numerous investigations into the seasonality of several autoimmune diseases and inflammatory bowel disease in an effort to better understand the epidemiology and pathogenesis of these conditions. However, the relationship between the season and disease activity of intestinal Behçet's disease has not been investigated. AIMS: This study aimed to evaluate the seasonal pattern of exacerbations of intestinal Behçet's disease. METHODS: We evaluated 268 consecutive patients with intestinal Behçet's disease who were diagnosed and treated between November 1990 and March 2010 at Severance Hospital, Yonsei University, Seoul, Korea. Patient demographics, onset of symptoms, total number of relapses, and the month of each relapse were recorded. The relationship between the season and flares of intestinal Behçet's disease was analyzed. RESULTS: A total of 339 relapses occurred in 142 patients (53 %). The median age at diagnosis was 39 (10-73) years; the median follow-up duration was 74 (7-372) months. The peak seasons for relapse were spring and autumn, especially the months of May and September (p value <0.001). Compared with winter, spring and autumn had higher rates of flares (HR 1.92 and 1.91, respectively, p value <0.001). CONCLUSIONS: In this study, intestinal Behçet's disease demonstrated a biphasic pattern (peaks in spring and autumn) in exacerbations of disease, suggesting that seasonal or exogenous factors may be involved in the flares of intestinal Behçet's disease.

Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet's disease on thiopurine maintenance.

BACKGROUNDS: The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD. METHODS: We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/µL) and nonleukopenic (n = 76, WBC count ≥ 4,000/µL) patients. RESULTS: The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan-Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively). CONCLUSION: Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet's disease.

Postoperative Effects of Thiopurines in Patients with Intestinal Behçet's Disease.

BACKGROUND: No studies have heretofore specifically focused on the efficacy of postoperative thiopurine therapy in intestinal Behçet's disease (BD). We conducted this study to assess the clinical effects of postoperative thiopurines in patients with intestinal BD. METHODS: We reviewed the medical records of all patients with intestinal BD who had undergone bowel resection surgery in a single tertiary academic medical center between 1991 and 2013. The cumulative probabilities of clinical recurrence were calculated using the Kaplan-Meier method, and predictive factors for recurrence were assessed by multivariate analysis. RESULTS: A total of 77 patients with intestinal BD received 5-ASA (n = 50, 64.9%) or thiopurine (n = 27, 35.1%) therapy after surgery at our center. The postoperative recurrence rate was lower in patients who received postoperative thiopurines (P = 0.050). The hazard ratio for recurrence was 0.636 (95% confidence interval 0.130-1.016, P = 0.053) for postoperative thiopurine use compared with postoperative 5-ASA. However, the rates of re-operation, re-admission, and death were not significantly different between the 5-ASA and thiopurine groups. CONCLUSIONS: Thiopurine therapy after surgery exhibited a modest effect in preventing recurrence in intestinal BD patients. More patients, long-term follow-up, and a randomized controlled design are necessary to validate the effectiveness of postoperative thiopurines in patients with this disease.

Differential expression of CD133 based on microsatellite instability status in human colorectal cancer.

The association between the types of genomic instability and cancer stem cell (CSC) has not been elucidated. We aimed to investigate the expressions of CSC markers with respect to microsatellite instability (MSI) status in human colorectal cancer (CRC). Immunostainings for CD133, CD44, and CD166, and K-ras mutation analysis were performed on 50 MSI-high (MSI-H), and 50 microsatellite stable (MSS) CRC tissues. In 11 MSS and MSI-H CRC cell lines, CD133 expression and DNA methylation statuses of the CD133 promoter were determined. The proportion of CD133 positive cells and the ability of colosphere formation were compared between HCT116 cells and HCT116 + Chr3 cells (hMLH1-restored HCT116 cells). Immunohistochemistry for CSC markers revealed that high CD133 expression was more frequent in MSS cancers than in MSI-H (P < 0.001, 74.0% vs. 28.0%, respectively), and related with short disease-free survival. Neither CD44 nor CD166 expression differed significantly with respect to MSI status. K-ras mutation showed no association with expressions of CD133, CD44, or CD166. CD133 expression was relatively high in the MSS cell lines compared to those in MSI-H, and showed a reverse correlation with DNA methylation of the CD133 promoter. hMLH1-restored HCT116 cells increased proportions of CD133 positive cells and colosphere forming ability, compared to those in HCT116 cells. In conclusion, high levels of CD133 expression were observed more frequently in MSS CRC than in MSI-H, suggesting that differential expression of colon CSC markers may be linked to tumor characteristics dependent on MSI status.