Suppressive effect of α-mangostin for cancer stem cells in colorectal cancer via the Notch pathway.

BACKGROUND: Since colon cancer stem cells (CSCs) play an important role in chemoresistance and in tumor recurrence and metastasis, targeting of CSCs has emerged as a sophisticated strategy for cancer therapy. α-mangostin (αM) has been confirmed to have antiproliferative and apoptotic effects on cancer cells. This study aimed to evaluate the selective inhibition of αM on CSCs in colorectal cancer (CRC) and the suppressive effect on 5-fluorouracil (5-FU)-induced CSCs. METHODS: The cell viability assay was performed to determine the optimal concentration of αM. A sphere forming assay and flow cytometry with CSC markers were carried out to evaluate the αM-mediated inhibition of CSCs. Western blot analysis and quantitative real-time PCR were performed to investigate the effects of αM on the Notch signaling pathway and colon CSCs. The in vivo anticancer efficacy of αM in combination with 5-FU was investigated using a xenograft mouse model. RESULTS: αM inhibited the cell viability and reduced the number of spheres in HT29 and SW620 cells. αM treatment decreased CSCs and suppressed the 5-FU-induced an increase in CSCs on flow cytometry. αM markedly suppressed Notch1, NICD1, and Hes1 in the Notch signaling pathway in a time- and dose-dependent manner. Moreover, αM attenuated CSC markers CD44 and CD133, in a manner similar to that upon DAPT treatment, in HT29 cells. In xenograft mice, the tumor and CSC makers were suppressed in the αM group and in the αM group with 5-FU treatment. CONCLUSION: This study shows that low-dose αM inhibits CSCs in CRC and suppresses 5-FU-induced augmentation of CSCs via the Notch signaling pathway.

Efficacy and safety of split-dose bowel preparation with 1 L polyethylene glycol and ascorbate compared with 2 L polyethylene glycol and ascorbate in a Korean population: a phase IV, multicenter, randomized, endoscopist-blinded study.

BACKGROUND AND AIMS: The 1-L polyethylene glycol (PEG)-based bowel preparation agent NER1006 (Plenvu; Norgine, Harefield, UK) has shown high cleansing efficacy and tolerability in clinical trials in Europe and North America. However, no clinical trials have yet been reported in Asia. Therefore, the aim of this study was to evaluate the efficacy and safety of 1L PEG-based bowel preparation with Plenvu compared with 2L PEG plus ascorbate bowel preparation in a Korean population. METHODS: In this multicenter, endoscopist-blinded, randomized study, patients at 9 hospitals in South Korea undergoing colonoscopy received either Plenvu or 2L PEG + ascorbate (2L PEG) with a split dose. The primary endpoint was overall bowel cleansing success (Boston Bowel Preparation Scale [BBPS] score ≥2 for all segments of the colon). Secondary endpoints were high-quality bowel cleansing success (overall, BBPS score = 9; segmental colon, BPPS score = 3), polyp detection rate (PDR), and adenoma detection rate (ADR). RESULTS: Of 360 included patients, cleansing efficacy was analyzed in 346 (Plenvu, 174; 2L PEG, 172). The Plenvu group showed noninferior bowel cleansing success rates compared with 2L PEG (93.10% vs 91.86%; difference, 1.24%; 1-sided 97.5% lower confidence limit, -4.31%; Pnoninferiority < .0001; Psuperiority = .661). The Plenvu group had higher high-quality bowel cleansing success rates for overall and right-sided colon segments than the 2L PEG group (49.43% vs 37.79% [P = .029] and 60.92% vs 48.84% [P = .024], respectively). The PDR was greater with Plenvu than with 2L PEG (48.85% vs 37.79%, P = .038). However, ADR did not differ between the 2 groups (24.71% vs 20.35%, P = .331). Although treatment-emergent adverse events (TEAEs) were slightly higher in the Plenvu group than in the 2L PEG group (65.71% vs 52.91%, P = .015), most TEAEs were mild (85.55%) and most patients recovered without any management (99.23%). CONCLUSIONS: Plenvu showed noninferior overall bowel cleansing success rates comparable with 2L PEG but greater high-quality bowel cleansing in overall and right-sided colon, which might help improve the PDR in the Asian population. (Clinical trial registration number: KCT0005894.).

Long-term prognosis of curative endoscopic submucosal dissection for early colorectal cancer according to submucosal invasion: a multicenter cohort study.

BACKGROUND: Endoscopic submucosal dissection (ESD) can provide a high en bloc resection rate and has been widely applied as curative treatment for early colorectal cancer (ECC). However, surgical treatment is occasionally required, and reports on the long-term prognosis of ESD are insufficient. This study aimed to investigate the long-term outcomes of ECC removal by ESD, including local recurrence and metastasis. METHODS: This multicenter study was conducted retrospectively on 450 consecutive patients with ECC who were treated with ESD between November 2003 and December 2013. Clinical, pathological, and endoscopic data were collected to determine tumor depth, resection margin, lymphovascular invasion, and recurrence. RESULTS: The median follow-up period was 53.8 (12-138 months). The en bloc resection rate was 85.3% (384) and in intramucosal cancer being 84.1% and in superficial submucosal invasion (SM1) cancer being 89.8% (p = 0.158). The curative resection rate was 76.0% (n = 342), and there was no statistical difference between the two groups (77.3% vs. 71.4%, p = 0.231). The overall recurrence free survival rate (RFS) was 98.7% (444/450). In patients with curative resection, there was no statistically significant difference in RFS according to invasion depth (intramucosal: 99.3% vs. SM1: 97.1%, p = 0.248). CONCLUSIONS: Patients with curatively resected ECC treated with ESD showed favorable long-term outcomes. Curatively resected SM1 cancer has a RFS similar to that of intramucosal cancer.

Clinical Course of COVID-19 in Patients with Inflammatory Bowel Disease in Korea: a KASID Multicenter Study.

In 2020, the novel coronavirus disease 2019 (COVID-19) began to spread worldwide and remains an ongoing medical challenge. This case series reports on the clinical features and characteristics of patients with inflammatory bowel disease (IBD) and confirmed COVID-19 infection. From February 2020 to March 2021, nine patients with IBD had confirmed COVID-19 across four hospitals in Korea. The median age at COVID-19 diagnosis was 42 years. Six patients were male, and seven patients had ulcerative colitis (UC). No patients required oxygen therapy, intensive care unit hospitalizations, or died. The most common symptom was fever, and gastrointestinal (GI) symptoms developed as diarrhea in five patients with UC. Oral steroids were used to combat UC aggravation in two patients. In this case series of nine IBD patients diagnosed with COVID-19 in Korea, the clinical presentation was predominately a mild respiratory tract infection. Most patients with UC developed new GI symptoms including diarrhea.

Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells.

(1) Background: six mammalian ceramide synthases (CerS1-6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22-C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. METHODS: We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2-2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/µL, levels of hemoglobin 10 g/dL, or platelet counts below 100 K/µL. RESULTS: Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (P=.005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22-0.81; P = .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P = .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. CONCLUSIONS: In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.

Impacts of age and sedation on cardiocerebrovascular adverse events after diagnostic GI endoscopy: a nationwide population-based study.

BACKGROUND AND AIMS: Data are limited regarding the impact of age and sedation on cardiocerebrovascular disease (CCD) adverse events after GI endoscopy. We investigated the incidence of and risk factors for CCD adverse events after diagnostic GI endoscopy and the impact of age and sedation on these unfavorable outcomes. METHODS: In this nationwide population-based study, the incidence of and risk factors for newly diagnosed CCD within 14 days after diagnostic endoscopy were analyzed using Health Insurance Review and Assessment Service data from January to December 2015. RESULTS: Among 1,943,150 subjects, CCD adverse events occurred in approximately 2.23% within 14 days after endoscopy. According to the performance of sedation during endoscopy (60.1% nonsedation vs 39.9% sedation, midazolam alone [96.4%]), the incidence rates of CCD adverse events (per 10,000 persons) were 275.8 versus 302.8 for EGD, 116.9 versus 143.8 for colonoscopy, and 230.4 versus 243.2 for EGD + colonoscopy, respectively. On multivariate analysis, older age (70-99 years) and sedation were independent risk factors for CCD adverse events. Regarding CCD risk stratified by age and sedation, older age had a significant impact on CCD adverse events in individuals who underwent EGD only or EGD + colonoscopy, but sedation did not. However, both older age and sedation had considerable influence on CCD adverse events in individuals who underwent colonoscopy only. Sedation during endoscopy was significantly associated with minor but not major CCD adverse events. CCD adverse events were significantly higher for inpatients. CONCLUSION: CCD adverse events after diagnostic endoscopy were significantly frequent in individuals with older age (70-99 years) and/or sedation during endoscopy. Stratification by age and sedation shows that the impact of these 2 factors on CCD adverse events differs according to endoscopy type.

Potential involvement of adiponectin in obesity-associated erosive esophagitis.

A strong causal relationship between obesity and erosive esophagitis has been proposed. Obesity may affect the pathogenesis of erosive esophagitis through adipokines as well as acid reflux. We evaluated the involvement of adiponectin in obesity-associated erosive esophagitis. In total, 1,902 patients who underwent endoscopy during medical check-ups were selected for study. Variables including the body mass index (BMI) and adiponectin level were compared between subjects with erosive esophagitis and normal controls. The subjects were classified by quartiles (Qs) of adiponectin level. Q4 was the reference group. The median adiponectin level differed by gender (men, 5.3 µg/ml vs women, 9.3 µg/ml; p<0.001). As the severity of erosive esophagitis increased in men, the BMI increased (p<0.001) while the adiponectin level decreased (p = 0.026). The multivariate odds ratio for erosive esophagitis was 1.79 for Q1, 1.73 for Q2, 2.34 for obesity, and 27.40 for hiatal hernia in men. When classified by obesity, the multivariate odds ratio for erosive esophagitis was 1.94 for Q1, 2.10 for Q2, and 18.47 for hiatal hernia only in obese men. In women, there were no trends in BMI, adiponectin levels, or severity of erosive esophagitis. We demonstrated that low adiponectin levels are involved in obesity-associated erosive esophagitis in men but not women.

High-Definition Chromoendoscopy Versus High-Definition White Light Colonoscopy for Neoplasia Surveillance in Ulcerative Colitis: A Randomized Controlled Trial.

OBJECTIVES: Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T). METHODS: This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared. RESULTS: There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 [7.0-43.3] minutes vs 16.5 [6.3-38.1] minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 [12-72]) compared with the HDCE-T group (9 [1-20]; P < 0.001). DISCUSSION: On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.

Gender Specific Differences in Prevalence and Risk Factors for Gastro-Esophageal Reflux Disease.

BACKGROUND: Gender-related factors might play an important role in the development of reflux esophagitis (RE) and symptomatic gastro-esophageal reflux disease (GERD). We aimed to evaluate the prevalence and risk factors for RE and symptomatic GERD and determine whether gender specific differences exist. METHODS: This study was conducted on a health cohort consisting of 10,158 participants who underwent comprehensive health screening. Lifestyles and gastrointestinal symptoms were investigated using a self-reported structured questionnaire. Questionnaires about menstrual status were added for the women. RESULTS: The prevalence of RE in men was significantly higher than that in women (10.6% vs. 2.0%, P < 0.001); however, symptomatic GERD showed predominance in women (6.2% vs. 2.5%, P < 0.001). Although the prevalence of RE gradually increased with the duration of menopause stratified by decade (P = 0.007), that of symptomatic GERD rapidly increased across the menopausal transit in women. Apart from common risk factors of obesity and current smoking for RE, over 70 years of age in women and hiatal hernia and hypertriglyceridemia in men were significant risk factors. In symptomatic GERD, high somatization was a common risk factor. Excessive alcohol drinking was a significant risk factor in men, but not in women. CONCLUSION: This study showed a predominance of RE in men, but a predominance of symptomatic GERD in women. In women, dynamic increase in the prevalence of GERD is closely related to the menopause conditions and its duration. There are specific risk factors for RE and symptomatic GERD according to gender differences.

Factors associated with pregnancy-related knowledge in women of reproductive age with inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel disease (IBD) usually develops at a young age, and many women experience marriage, pregnancy, and delivery during the disease course. We aimed to evaluate the pregnancy-related knowledge of women with IBD in Korea and investigate the associated factors. MATERIAL AND METHODS: A total of 270 women with IBD, aged 19-45 years, from four tertiary hospitals in Korea were administered a questionnaire comprising 17 questions from the validated Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow) that were translated into Korean. RESULTS: The average CCPKnow score of the 270 patients was 7.47 ± 3.07; and most of the patients (51.5%) exhibited a poor knowledge level. Younger age at diagnosis, Crohn's disease rather than ulcerative colitis, longer disease duration, anti-TNF-α medication history, higher household income, and delivery after diagnosis were associated with an appropriate level of pregnancy-related knowledge. Younger age at diagnosis (odds ratio [OR], 1.87; p = .036), anti-TNF-α therapy (OR, 1.87; p = .047), and delivery while suffering from IBD (OR, 3.07; p = .002) were independent factors affecting the pregnancy-related knowledge level. Approximately 69.6% of patients acquired related knowledge from their gastroenterology doctor, whereas 19.4% of patients intended to remain childless. CONCLUSIONS: To our knowledge, this is the first study to assess the pregnancy-related knowledge of women of reproductive-age with IBD and their perceptions by using a questionnaire in Asia. As more than half of the patients showed a poor knowledge level of IBD, a general education program should be conducted by gastroenterology doctors.

Triple therapy versus sequential therapy for the first-line Helicobacter pylori eradication.

BACKGROUND: The eradication rate of Helicobacter pylori (H. pylori) with triple therapy which was considered as standard first-line treatment has decreased to 70-85%. The aim of this study is to compare 7-day triple therapy versus 10-day sequential therapy as the first line treatment. METHODS: Data of 1240 H. pylori positive patients treated with triple therapy or sequential therapy from January 2013 to December 2015 were analyzed retrospectively. The patients who had undertaken previous H. pylori eradication therapy or gastric surgery were excluded. RESULTS: There were 872 (74.3%) patients in the triple therapy group, and 302 (25.7%) patients in the sequential therapy group. There was no significant difference between the two groups regarding age, residence, comorbidities or drug compliance, but several differences were noted in endoscopic characteristics and indication for the treatment. The eradication rate of H. pylori by intention to treat analysis was 64.3% in the triple therapy group, and 81.9% in the sequential therapy group (P = 0.001). In per protocol analysis, H. pylori eradication rate in the triple therapy and sequential therapy group was 81.9 and 90.3%, respectively (P = 0.002). There was no significant difference in overall adverse events between the two groups (P = 0.706). For the rescue therapy, bismuth-containing quadruple therapy showed comparable treatment efficacy after sequential therapy, as following triple therapy. CONCLUSIONS: The eradication rate of triple therapy was below the recommended threshold. Sequential therapy could be effective and tolerable candidate for the first-line H. pylori eradication therapy.

Multidisciplinary Approach to Refractory Upper Gastrointestinal Bleeding: Case Series of Angiographic Embolization.

Although medical and endoscopic hemostasis is now considered as the first-line therapy for nonvariceal upper gastrointestinal (UGI) bleeding, refractory bleeding still occurs in 5%-10% of the patients. In these patients, transcatheter arterial embolization (TAE) or surgery is required, but research on embolization for unmanageable UGI bleeding in Korea is scanty. We reviewed the medical records of 518 patients who underwent endoscopic hemostasis during 4 years. Among these subjects, 8 patients who required embolization due to failure of endoscopic hemostasis were enrolled. Mean patient age was 74.00 ± 8.25 years, and rebleeding occurred in 4 patients within 48 hours after TAE. Three patients with duodenal rebleeding underwent surgery, and the other patient with a gastric ulcer underwent endoscopic hemostasis. Nonvariceal UGI bleeding remains a serious clinical challenge, especially in older patients. A multidisciplinary approach including endoscopists, interventional radiologists, and surgeons may be important for the treatment of nonvariceal UGI bleeding.

Long-Term Clinical Outcomes of Rectal Neuroendocrine Tumors According to the Pathologic Status After Initial Endoscopic Resection: A KASID Multicenter Study.

OBJECTIVES: With advances in diagnostic endoscopy, the detection of rectal neuroendocrine tumors (NETs) has increased. However, clinical outcomes, especially after endoscopic treatment, are still unclear. The aim of this study was to determine the long-term clinical outcomes of endoscopically resected rectal NETs according to the pathologic status after initial resection. METHODS: In this large, multicenter, retrospective cohort study, we analyzed the medical records of patients who underwent endoscopic resection of rectal NETs and were followed for ≥24 months at 16 university hospitals. The outcomes of interest were local or distant recurrence and metachronous lesions. RESULTS: On the pathologic assessment of 407 patients, the resection margin status was positive in 76 (18.7%) and indeterminate in 72 (17.7%) patients. Patients whose rectal NETs were diagnosed or suspected as NETs before resection showed a much higher complete resection rate than those whose tumors were resected as polyps and then diagnosed (P<0.001). Fourteen patients received salvage treatment at 1.9±2.8 months after initial treatment. During a median follow-up period of 45.0 months, local recurrence occurred in 3 (0.74%) patients, but there was no recurrence in the lymph nodes or distant organs. Metachronous rectal NETs were diagnosed in 3 (0.74%) patients. According to the pathologic status after initial resection, local recurrence and metachronous lesions occurred in 1 (0.4%) and 2 (0.8%) patients, respectively, in the pathologic tumor-free group, whereas they occurred in 2 (1.4%) and 1 (0.7%) patients, respectively, in the indeterminate group. CONCLUSIONS: Considering the long-term prognosis including that for recurrences or metachronous lesions, endoscopic resection is an efficient and a safe modality for the treatment of rectal NETs. This treatment may result in favorable clinical outcomes in patients with tumors of indeterminate pathology, as well as in pathologic tumor-free cases after initial resection.

Prediction model and risk score for perforation in patients undergoing colorectal endoscopic submucosal dissection.

BACKGROUND AND AIMS: Perforation is the adverse event of greatest concern during colorectal endoscopic submucosal dissection (ESD). Accurate risk prediction of perforation may enable prevention strategies and selection of the most efficient therapeutic option. This study aimed to develop and validate a risk prediction model for ESD-induced perforation. METHODS: A multicenter cross-sectional study was performed on 2046 patients who underwent colorectal ESD at 9 Korean ESD Study Group-affiliated hospitals. The enrolled patients were randomly divided into either a derivation set or a validation set. In the derivation set, a prediction score was constructed to assess the risk of perforation using preoperative and procedural-related predictors selected via logistic regression. Discrimination and calibration of the prediction model was assessed using the validation set. RESULTS: An ESD-induced perforation occurred in 135 patients (6.6%). In the derivation set, multivariate logistic regression identified endoscopist experience (≥50 ESDs: odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.35-1.00), tumor size (+1-cm increments: OR = 1.39; 95% CI, 1.19-1.62), colonic location (OR = 2.20; 95% CI, 1.24-3.89), and submucosal fibrosis (OR = 2.00; 95% CI, 1.04-3.87) as predictive factors (C-statistic = 0.678; 95% CI, 0.617-0.739). In the validation set, the model showed good discrimination (C-statistic = 0.675; 95% CI, 0.615-0.735) and calibration (P = .635). When a simplified weighted scoring system based on the OR was used, risk of perforation ranged from 4.1% (95% CI, 2.8%-5.9%) in the low-risk group (score ≤4) to 11.6% (95% CI, 8.5%-15.6%) in the high-risk group (score >4). CONCLUSIONS: This study developed and internally validated a score consisting of simple clinical factors to estimate the risk of colorectal ESD-induced perforation. This score can be used to identify patients at high risk before colorectal ESD.

Importance of Patients' Knowledge of Their Prescribed Medication in Improving Treatment Adherence in Inflammatory Bowel Disease.

GOALS: To investigate the association between treatment nonadherence and patients' knowledge of the prescribed medication among individuals with inflammatory bowel disease (IBD), and evaluate the impact of nonadherence on relapse. BACKGROUND: The patient's knowledge of the prescribed medication has been identified as an important predictor of treatment adherence in chronic diseases. However, this association has not been examined in IBD. STUDY: In this prospective study, at baseline, 138 patients with IBD completed a self-reported survey on demographic data, knowledge of the prescribed medication, and candidate factors related to the degree of treatment adherence. To investigate the impact of nonadherence among patients in remission, relapse was analyzed for 18 months after enrollment. RESULTS: Nonadherence was observed in 50 (36.2%) of the 138 subjects. In multivariate analysis, nonadherence was significantly associated with younger age (less than 30 y) at participation [odds ratio (OR), 5.88; 95% confidence interval (CI), 1.51-22.94; P=0.011], longer intervals between outpatient clinic visits (≥3 mo) (OR, 30.31; 95% CI, 3.06-300.17; P=0.004), and limited knowledge of the prescribed medication (OR, 5.61; 95% CI, 1.60-19.67; P=0.038). Nonadherent patients had a significantly greater risk of relapse of IBD than adherent patients (relative risk, 2.9; 95% CI, 2.25-3.79; P=0.045). CONCLUSION: Younger age, longer intervals between outpatient clinic visits, and limited knowledge of the prescribed medication tended to be associated with nonadherence to treatment, which consequently also affects the risk of relapse.

Significance of calcium-sensing receptor expression in gastric cancer.

OBJECTIVE: The calcium-sensing receptor (CaSR) is known to have differential expression in various carcinomas and normal tissues. It has been shown to be involved in carcinogenesis or tumor suppression. However, its role in gastric cancer remains unknown. This study was performed to determine the CaSR expression level in gastric cancer and non-tumor gastric tissues and to examine the related clinicopathological factors. MATERIALS AND METHODS: Thirty-one pairs of gastric cancer tissues and matched non-tumor gastric tissues were obtained from surgical tissues after gastrectomy. Using real-time polymerase chain reaction, we measured CaSR mRNA expression. We evaluated the association between CaSR mRNA expression and clinicopathological variables based on the downregulation or upregulation of CaSR mRNA expression in gastric cancer tissues compared to those of matched non-tumor gastric tissues. By immunohistochemistry, we confirmed CaSR expression levels in gastric cancer tissues. RESULTS: Downregulation of CaSR mRNA was observed in 77.4% of gastric cancer tissues compared to their matched normal tissues. Downregulated CaSR was associated with a tendency for deeper invasion into the proper muscle (p = 0.028) and more advanced stage (II-IV; p = 0.012). CONCLUSION: We conclude that downregulation of CaSR may contribute to the prevention or suppression of tumor outgrowth.

CCN1 secreted by tonsil-derived mesenchymal stem cells promotes endothelial cell angiogenesis via integrin αv ß3 and AMPK.

CCN1 is highly expressed in cancer cells and has been identified in the secretome of bone marrow-derived mesenchymal stem cells (BM-MSC). Although secreted CCN1 is known to promote angiogenesis, its underlying mechanism remains unclear. Here, we examined whether our recently-established tonsil-derived MSC (T-MSC) secrete CCN1 and, if any, how CCN1 promotes the angiogenesis of human umbilical vein endothelial cells (HUVEC). Compared with untreated control T-MSC, a higher level of CCN1 was secreted by T-MSC treated with activin A and sonic hedgehog, drugs known to induce endodermal differentiation. Expectedly, conditioned medium collected from differentiated T-MSC (DCM) significantly increased HUVEC migration and tube formation compared with that from control T-MSC (CCM), and these stimulatory effects were reversed by neutralization with anti-CCN1 antibody. Treatment with recombinant human CCN1 (rh-CCN1) alone also mimicked the stimulatory effects of DCM. Furthermore, treatment with either DCM or rh-CCN1 increased the phosphorylation of AMP kinase (AMPK), and ectopic expression of siRNA of the AMPK gene inhibited all observed effects of both DCM and rh-CCN1. However, no alteration of intracellular ATP levels or phosphorylation of LKB1, a well-known upstream factor of AMPK activation, was observed under our conditions. Finally, the neutralization of integrin α(v) ß(3) with anti-integrin α(v) ß(3) antibody almost completely reversed the effects of CCN1 on AMPK phosphorylation, and EC migration and tube formation. Taken together, we demonstrated that T-MSC increase the secretion of CCN1 in response to endodermal differentiation and that integrin α(v) ß(3) and AMPK mediate CCN1-induced EC migration and tube formation independent of intracellular ATP levels alteration.

Risks for opportunistic tuberculosis infection in a cohort of 873 patients with inflammatory bowel disease receiving a tumor necrosis factor-α inhibitor.

OBJECTIVE: Real-world epidemiological data on tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) receiving TNF-α inhibitors are scarce. We investigated the risks for and case characteristics of TB in a large cohort of IBD patients treated with TNF-α inhibitors in Korea, where TB is endemic. MATERIALS AND METHODS: We performed an observational study on all TB cases identified in a cohort of 873 IBD subjects treated with TNF-α inhibitors from January 2001 to December 2013. The standardized incidence ratio (SIR) of TB was calculated using data from the matched general population. RESULTS: A total of 25 newly developed TB cases were identified in the cohort (pulmonary TB, 84% [21/25]; extrapulmonary TB, 16% [4/25]). The adjusted SIR of TB was 41.7 (95% confidence interval, 25.3-58.0), compared with that of the matched general population. Nineteen of the 25 patients (76%) developed TB within 2-62 months of initiation of TNF-α inhibitor treatment despite screening negative for latent TB infection (LTBI), whereas three patients with LTBI (12%, 3/25) developed TB 3 months after completion of chemoprophylaxis. The outcomes of TB treatment were mostly favorable, although one death from peritoneal TB was noted. The type of TNF-α inhibitor prescribed (infliximab) was a significant predictor of TB (p = 0.033). CONCLUSIONS: TNF-α inhibitor treatment strikingly increases the risk of TB infection in an IBD population from a TB endemic area. Continuous evaluation of the development of de novo TB infection in IBD patients subjected to long-term TNF inhibitor therapy is mandatory.

The use of low-volume polyethylene glycol containing ascorbic acid versus 2 L of polyethylene glycol plus bisacodyl as bowel preparation for colonoscopy.

OBJECTIVE: Low-volume polyethylene glycol (PEG) bowel preparations have been developed to improve compliance for colonoscopy. Our study aimed to compare the efficacy and tolerability of low-volume PEG containing ascorbic acid for colonoscopy against 2 L of PEG plus bisacodyl. METHODS: We prospectively enrolled consecutive inpatients who had not undergone polypectomy at the index colonoscopy and were subsequently referred for polypectomy at our hospital. A total of 62 patients were randomized to receive either low-volume PEG containing ascorbic acid (n = 31) or 2 L of PEG plus bisacodyl (n = 31) as a split-dose regimen in inpatients. The efficacy of preparation was determined using the Ottawa Bowel Preparation Score (OBPS) and a 4-point scale. Adverse events, tolerability, and willingness were evaluated using a questionnaire. RESULTS: Based on the OBPS and 4-point scale, we determined that the efficacy of low-volume PEG containing ascorbic acid was comparable to that of the 2 L of PEG plus bisacodyl (p = 0.071 for OBPS, p = 0.056 for the 4-point scale). Adverse events were comparable between the two groups (p = 1.000). A greater proportion of patients in the low-volume PEG containing ascorbic acid (90.6%) and the 2L of PEG plus bisacodyl (96.9%) were willing to repeat the same preparation for subsequent colonoscopy. CONCLUSION: Low-volume PEG containing ascorbic acid had comparable efficacy and tolerability to 2 L of PEG plus bisacodyl, when given as a split dose, for colonoscopy in inpatients. Split-dose low-volume PEG containing ascorbic acid is a good alternative for bowel preparation for colonoscopy in inpatients.