Safety and effectiveness of additional triamcinolone acetonide with endoscopic radial incision and cutting for benign stenosis of the lower gastrointestinal tract: A pilot study.

Objectives: Radial incision and cutting (RIC) is being investigated as an alternative endoscopic dilation method for lower intestinal tract stenosis, providing a high technical success rate and improving subjective symptoms. However, several patients develop re-stenosis following RIC. In this pilot study, we aimed to evaluate the safety and efficacy of triamcinolone acetonide (TA) addition after RIC. Methods: RIC with TA was performed in 20 patients with lower gastrointestinal tract stenosis. We evaluated the rate of adverse events 2 months after RIC with TA. We investigated the short- and long-term prognoses, as well as the improvement in subjective symptoms, using a visual analog scale. Results: The delayed bleeding rate after RIC was 23.8%. Endoscopic hemostasis was achieved in all patients with delayed bleeding. No perforations were observed. The cumulative re-stenosis-free, re-intervention-free, and surgery-free rates 1 year after RIC were 52.9%, 63.7%, and 85.2%, respectively. Subjective symptoms, including abdominal pain, abdominal bloating, nausea, and dyschezia, significantly improved after RIC with TA. Conclusion: Although additional TA administration after RIC could be safe, additional TA may not be effective on luminal patency after dilation. Further investigation is warranted.

Endoscopic radial incision and cutting for benign stenosis of the lower gastrointestinal tract: An investigation of novel endoscopic treatment in multicenter trial.

BACKGROUND AND AIM: The standard therapies for benign gastrointestinal stenosis are endoscopic balloon dilation or surgery; each have their advantages and disadvantages. In contrast, radial incision and cutting (RIC) is a novel approach for such stenosis. This study aimed to investigate the feasibility, safety, and effectiveness of RIC. METHODS: We enrolled 20 patients with benign stenosis of the lower gastrointestinal tract developed by various causes and conducted RIC. We evaluated the re-intervention free rate 52 weeks after RIC, technical success rate, adverse events, procedure time, and improvement of symptoms using a visual analog scale. RESULTS: We performed 20 sessions of first RIC for 20 lesions and seven sessions of additional RIC due to re-stenosis. The cumulative re-intervention-free survival rate 52 weeks after the first RIC was 55.8%. The technical success rate of the first RIC was 100% (20/20) while that of the additional RIC was 85.7% (6/7). One case developed perforation during the additional RIC and urgent surgery was performed. The additional RIC tended to show worse results in adverse events and procedure time compared with the first RIC. The patients' symptoms including abdominal bloating and dyschezia were significantly improved. CONCLUSIONS: Although RIC demonstrated a higher technical success rate for lower gastrointestinal stricture and subsequent improvement of patient symptoms, several issues including preventing delayed bleeding, perforation, and the long-term prognosis should be solved and clarified in further investigations.

Long-term course of inflammatory bowel disease after the Great East Japan Earthquake.

BACKGROUND AND AIM: This study analyzed inflammatory bowel disease activity for 2 years after the Great East Japan Earthquake. METHODS: We compared the relapse rates of patients with ulcerative colitis or Crohn's disease 1 and 2 years after the earthquake with rates immediately after the earthquake. To evaluate continuous disease courses, we also performed multivariate time-to-event analyses from the time of the earthquake to the onset of additional treatments. RESULTS: Of 903 patients with ulcerative colitis or Crohn's disease in our previous study, we could evaluate 2-year courses in 677 patients (394 ulcerative colitis and 283 Crohn's disease). Compared with the relapse rates of ulcerative colitis and Crohn's disease immediately after the earthquake (15.8% and 7.0%, respectively), those in the corresponding periods in 2012 (2.5% and 1.1%, respectively) and 2013 (2.3% and 2.5%, respectively) significantly decreased. There were 226 patients who required additional treatments after the earthquake. Multivariate time-to-event analyses revealed that only patients who had experienced the death of family members or friends were likely to need additional treatments (hazard ratio = 1.77, 95% confidence interval = 1.25-2.47). No other factors had a significant influence. CONCLUSIONS: The relapse rates 1 and 2 years after the earthquake significantly decreased. The factors that influenced long-term relapse were different from those that influenced short-term relapse.

Management of aorto-esophageal fistula secondary after thoracic endovascular aortic repair: a review of literature.

Aorto-esophageal fistula (AEF) is a rare and lethal entity, and the difficulty of making diagnosis of AEF is well-known. As promising results in the short-term effectiveness of thoracic endovascular aortic repair (TEVAR) promote its usage, the occurrence of AEF after TEVAR (post-TEVAR AEF) increases as one of the major complications. Therefore, we provide a review concerning the management strategy of post-TEVAR AEF. Although its representative symptom was reported as the triad of mid-thoracic pain and sentinel hematemesis followed by massive hematemesis, the symptom-free interval between sentinel hemorrhage and massive exsanguination is unpredictable. However, the physiological condition represents a surgical contraindication. Accordingly, early diagnosis is important, but either CT or esophago-gastro-duodenoscopy rarely depicts a typical image. The formation of post-TEVAR AEF might be associated with the infection of micro-organisms, which is uncontrollable with anti-biotic administration. The current first-line strategy is combination therapy as follows, (1) to control bleeding by TEVAR in the urgent phase, and (2) radical debridement and aortic/esophageal re-construction in the semi-urgent phase. In view of the high mortality and morbidity rate, it is proposed that the choice in treatment strategies might be affected by patient`s condition, size of the wall defects and the etiology of AEF. Practically, we should keep in mind the importance of making an early diagnosis and, once a suspicious symptom has occurred in a patient with a history of TEVAR, the existence of post-TEVAR AEF should be suspected. A prospective registry together with more developed technologies will be needed to establish a future strategy.

MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6.

AIM: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression. CONCLUSION: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection.

Endoscopic submucosal dissection for colorectal neoplasia during the clinical learning curve.

BACKGROUND: The efficacy of colorectal endoscopic submucosal dissection (ESD) has been reported mainly from Japanese referral centers. However, ESD is technically difficult and associated with a higher risk of adverse events than endoscopic mucosal resection, especially for novices performing colorectal ESD with little experience in gastric ESD. The current study evaluated the results of colorectal ESD during the clinical learning curve by retrospectively examining the results of colorectal ESD performed by four endoscopists who had experience with fewer than five cases of gastric ESD. METHODS: The study retrospectively investigated the first 20 cases managed by each endoscopist, for a total of 80 cases. The main outcome measurements were procedural time, en bloc resection rate with tumor-free margins (R0 resection rate), and adverse events rate. From among clinicopathologic characteristics, factors that affected main outcome measurements were identified. RESULTS: Of the 80 cases (56 colonic and 24 rectal lesions; 44 granular laterally spreading tumors (LSTs) and 23 nongranular LSTs, 5 depressed, and 8 protruding), 54 cases (67.5%) had resection using a standard tip-type knife, and 26 cases (32.5%) had resection using a small scissors-type knife. The mean tumor diameter was 34.9 ± 14.1 mm, and the mean procedural time was 108.8 ± 53.4 min. The resection in 75 cases (93.8%) was performed en bloc, and the R0 resection rate was 75% (60/80). Perforation occurred in six cases (7.5%) and postoperative hemorrhage in three cases (3.8%). Multivariate analyses showed that colonic lesions and larger lesions (≥40 mm) were significantly associated with prolonged procedural time (≥90 min). Use of the scissors-type knife was significantly associated with a higher R0 resection rate. Perforation occurred only in colonic lesions. CONCLUSIONS: For novices in colorectal ESD, beginning with rectal and smaller lesions may be advisable. Also, using scissors-type knives may increase the R0 resection rate.

Modulation of endoplasmic reticulum (ER) stress-induced autophagy by C/EBP homologous protein (CHOP) and inositol-requiring enzyme 1α (IRE1α) in human colon cancer cells.

To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1α (IRE1α) and C/EBP homologous protein (CHOP) were involved in the ER stress-autophagy pathway, and CHOP was a regulator of IRE1α protein expression. Our findings suggest that CHOP promotes IRE1α and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress-autophagy pathway.

FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn's disease through affecting the ADCC activity.

An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn's disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn's disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A-158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients.

Short and long-term outcomes of endoscopic balloon dilatation for Crohn's disease strictures.

AIM: To investigate the short and long-term outcomes of endoscopic balloon dilatation (EBD) for Crohn's disease (CD) strictures. METHODS: Between January 1995 and December 2011, 47 EBD procedures were performed in 30 patients (8 females and 22 males) with CD. All patients had strictures through which an endoscope could not pass, and symptoms of these strictures included abdominal pain, abdominal fullness, nausea, and/or vomiting. The 47 strictures included 17 anastomotic and 30 de novo strictures. Endoscopy and dilatation were performed under conscious sedation with intravenous diazepam or flunitrazepam. The dilatations were all performed using through-the-scope balloons with diameters from 8 mm to 20 mm on inflation and lengths of 30-80 mm. Each dilatation session consisted of two to four, 3-min multistep inflations of the balloon, repeated at intervals of 1 wk until adequate dilatation (up to 15-20 mm in diameter) was achieved. The follow-up data were collected from medical records and analyzed retrospectively. Primary success was defined as passage of the scope through the stricture after EBD. Long-term outcomes were analyzed focusing on intervention-free survival and surgery-free survival demonstrated by the Kaplan-Meier method. (Intervention-free meant cases in which neither endoscopic balloon re-dilatation nor surgery was needed after the first dilatation during the observation period). The log rank test was used to evaluate the difference in long-term outcomes between anastomotic and de novo stricture cases. RESULTS: Primary success was achieved in 44 of the 47 strictures (93.6%). Balloon dilatations failed in 3 cases (6.4%). In 1 case, EBD was a technical failure because the guide-wire could not be passed through the stricture which showed severe adhesion and was a flexural lesion of the intestine. In 2 cases, unexpected perforations occurred immediately after balloon dilatation. Of the 47 treatments, complications occurred in 5 (10.6%). All 5 patients had de novo strictures. One suffered bleeding, two high fever and there were colorectal perforations. One of the patients with a colorectal perforation was treated surgically, the other was managed conservatively. These 2 cases correspond to the two aforementioned EBD failures. Long-term outcomes were evaluated for the 44 successfully-treated strictures after a median follow-up of 26 mo (range, 2-172 mo). During the observation period, re-strictures after EBDs occurred in 26 cases (60.5%). Fourteen of these 26 re-stricture cases underwent EBD again, but in two EBD failed and surgery was ultimately performed in both cases. Twelve of the 26 re-stricture cases were initially treated surgically when the re-strictures occurred. Finally, 30 of the 47 strictures (63.8%) were successfully managed with EBD, allowing surgery to be avoided. Intervention-free survival evaluated by the Kaplan-Meier method was 75% at 12 mo, 58% at 24 mo, and 43% at 36 mo. There was no significant difference between the anastomotic strictures (n = 16) and de novo strictures (n = 28) in the intervention-free survival as evaluated by the log-rank test. Surgery-free survival evaluated by the Kaplan-Meier method was 90% at 12 mo, 75% at 24 mo, and 53% at 36 mo. The 16 anastomotic strictures were associated with significantly better surgery-free survivals than the 28 de novo strictures (log-rank test: P < 0.05). CONCLUSION: Anastomotic strictures were associated with better long-term outcomes than de novo strictures, indicating that stricture type might be useful for predicting the long-term outcomes of EBD.

Prognostic and diagnostic significance of tumor budding associated with ß-catenin expression in submucosal invasive colorectal carcinoma.

Endoscopic resection has become a major curative treatment for early colorectal carcinoma without lymph node metastasis. However, lymph node metastasis, a poor prognostic factor in colorectal carcinoma, occurs in about 10% of the patients with submucosal invasive colorectal carcinoma. Therefore, it is important to identify a high-risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma. This study was designed to identify the relationship between tumor budding with ß-catenin expression and lymph node metastasis in submucosal invasive colorectal carcinoma. We investigated the immunohistochemistry of tumor budding in the 142 patients who underwent surgical resection for submucosal invasive colorectal carcinomas between 1984 and 1999 and the expression pattern of ß-catenin in budding tumor cells. Accordingly, all the patients were followed up for at least 10 years or until death. Among the 142 patients, lymph node metastasis was detected in 14 patients (9.9%). Univariate analysis showed that tumor budding with ≥ 5 tumor cells or cell clusters with expression of ß-catenin in the nucleus was significantly associated with lymph node metastasis (P = 0.005). In contrast, tumor budding detected by hematoxylin and eosin staining was not associated with lymph node metastasis. Multivariate logistic regression analysis showed that tumor budding with ≥ 5 tumor cells or cell clusters with expression of ß-catenin in the nucleus was a significant risk factor for lymph node metastasis (odds ratio, 7.124; 95% confidence interval, 1.407-36.062). Thus, tumor budding associated with ß-catenin expression is a risk factor for lymph node metastasis in submucosal invasive colorectal carcinoma.

Changes of faecal microbiota in patients with Crohn's disease treated with an elemental diet and total parenteral nutrition.

BACKGROUND: Intestinal microbiota contributes to the pathogenesis of Crohn's disease. Elemental diet and total parenteral nutrition are effective therapies for Crohn's disease; however, changes of microbiota as a result of both treatments have not been fully elucidated. AIM: To elucidate changes of faecal microbiota in Crohn's disease patients treated with elemental diet and total parenteral nutrition. METHODS: Stool samples were collected from 33 active Crohn's disease patients and 17 healthy subjects, and recollected after elemental diet (8 patients) and total parenteral nutrition (9 patients). Terminal restriction fragment length polymorphism analysis of bacterial 16srDNA was performed to evaluate the whole microbiota. Specific quantitative PCR was then used to determine populations of predominant bacterial groups. RESULTS: In Crohn's disease patients, the number of terminal restriction fragments, which reflects bacterial species, was significantly lower. Populations of total bacteria and Bifidobacterium were significantly lower and the ratio of Enterococcus was higher. The number of terminal restriction fragments was significantly decreased after total parenteral nutrition, but not after elemental diet. Population of Bacteroides fragilis significantly decreased after elemental diet, while population of Enterococcus significantly increased after total parenteral nutrition. CONCLUSION: Faecal microbiota in Crohn's disease patients was markedly different from healthy subjects. Species diversity was reduced by total parenteral nutrition, but not by elemental diet.

[Clinical courses and pregnancy outcomes in Japanese women with inflammatory bowel disease].

In this study, we analyzed the clinical courses and the pregnancy outcomes in Japanese women with inflammatory bowel disease (IBD) in our hospital in the recent 10 years. We analyzed 49 pregnancies in 38 patients with ulcerative colitis (UC) and 24 pregnancies in 16 patients with Crohn's disease (CD) retrospectively. The results indicated that pregnancy has less influence on the clinical courses of IBD and that IBD also has less influence on the pregnancy outcomes. However, we should pay attention to the results that the patients with CD tend to deteriorate if conception occurs when CD is active and that patients with active UC tend to have more adverse pregnancy outcomes than patients in remission. In conclusion, patients with IBD are recommended to become pregnant when the diseases are in remission and treatment using selected safe medications should be continued during the pregnancy.

Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa.

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.

Scheduled maintenance therapy with infliximab improves the prognosis of Crohn's disease: a single center prospective cohort study in Japan.

The main goal of Crohn's disease (CD) treatment at present is to induce and maintain remission for as long as possible, and several approaches have been used as induction and maintenance therapies. There are no reports that have compared the effects on mid- and long-term prognosis among the induction and maintenance therapies, especially between infliximab, a chimeric antibody to tumor necrosis factor-alpha, and nutritional therapies. A total of 262 CD patients with induced remission were enrolled in the cohort study. Patients who failed to achieve remission, and patients who were lost to follow-up within 12 months were excluded. Induction therapies for CD included total elemental enteral nutrition, total parenteral nutrition, infliximab, prednisolone, and surgical resection. Maintenance therapies included home elemental diet, 5-aminosalicylates, immunomodulators, and scheduled infliximab therapy. We evaluated the possible predictive factors of relapse and surgical recurrence including the clinical backgrounds of the patients and medical therapies, using the Cox multivariate hazard analysis. The main factors that strongly affected the first relapse were scheduled infliximab therapy (hazard ratio (HR) = 0.24, p < 0.0001), surgical induction (HR = 0.19, p < 0.0001) and high frequency of previous relapse (HR = 2.56, p = 0.002). Penetrating (HR = 3.33, p = 0.009) and stricturing (HR = 6.60, p < 0.0001) disease behavior were main risk factors of surgical recurrence. Scheduled infliximab therapy is the most effective maintenance therapy in a real clinical setting with respect to the mid- and long-term prognosis.

Involvement of NF-kappa B pathway in TL1A gene expression induced by lipopolysaccharide.

BACKGROUNDS: Recent studies have shown that TL1A (TNFSF15) is one of the definitive susceptibility genes to Crohn's disease (CD). To determine the immunological contribution of TL1A to CD, it is essential to investigate the transcriptional regulation of TL1A. METHODS/RESULTS: We analyzed the transcriptional mechanisms of TL1A induced by lipopolysaccharide (LPS) using the human monocytic cell line U937. RT-PCR revealed that LPS induced TL1A mRNA expression. Transient transfection assays using the promoter-reporter construct which contained 5' flanking region of TL1A revealed that LPS induce transcription of TL1A. Serial deletion constructs revealed that the positive regulatory elements involved with LPS-induced transcriptional activation were located between -247 and -135 in TL1A, in which one putative NF-kappa B binding site was predicted. Overexpressions of I-kappa Balpha inhibited LPS-induced transcriptional activation. Mutation of the predicted NF-kappa B binding site abolished the LPS-induced transcriptional activation. The binding of NF-kappa B to the predicted NF-kappa B motif was demonstrated by electrophoretic mobility shift assays. CONCLUSION: (1) LPS induces TL1A expression through the transcriptional activation via a NF-kappa B pathway. (2) The NF-kappa B binding site in the 5' flanking region of TL1A was identified.