Lee Guan Lim

Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease

Objectives Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD. Methods Confocal endomicroscopy was performed in IBD and control patients using intravenous fluorescein to determine the relationship between cell shedding and local barrier dysfunction. A grading system based on appearances at confocal endomicroscopy in humans was devised and used to predict relapse in a prospective pilot study of 47 patients with ulcerative colitis and 11 patients with Crohns disease. Results Confocal endomicroscopy in humans detected shedding epithelial cells and local barrier defects as plumes of fluorescein effluxing through the epithelium. Mouse experiments demonstrated inward flow through some leakage-associated shedding events, which was increased when luminal osmolarity was decreased. In IBD patients in clinical remission, increased cell shedding with fluorescein leakage was associated with subsequent relapse within 12 months after endomicroscopic examination (p<0.001). The sensitivity, specificity and accuracy for the grading system to predict a flare were 62.5% (95% CI 40.8% to 80.4%), 91.2% (95% CI 75.2 to 97.7) and 79% (95% CI 57.7 to 95.5), respectively. Conclusions Cell shedding and barrier loss detected by confocal endomicroscopy predicts relapse of IBD and has potential as a diagnostic tool for the management of the disease.

Intragastric balloon significantly improves nonalcoholic fatty liver disease activity score in obese patients with nonalcoholic steatohepatitis: a pilot study

BACKGROUND There is no satisfactory treatment for nonalcoholic steatohepatitis (NASH). The Bioenterics intragastric balloon (BIB) can be an effective treatment for weight reduction in obese patients. OBJECTIVE We evaluated the efficacy of the BIB in improving the histology of NASH in obese patients. DESIGN Randomized, controlled study. SETTING University hospital. PATIENTS Obese patients with body mass indexes (BMI) ≥27 kg/m(2) and who had histologic evidence of NASH were recruited. INTERVENTION Patients were randomly assigned to a step 1 American Heart Association (AHA) diet plus exercise and BIB placement or step 1 AHA diet plus exercise and sham BIB placement for a period of 6 months. MAIN OUTCOME MEASUREMENTS Liver histology was the primary outcome measure recorded before and after treatment. RESULTS A total of 18 patients completed the study. Baseline characteristics of the BIB and sham groups were similar. At 6 months, a significant reduction in the mean BMI was seen in the BIB group (1.52 vs 0.8; P = .0008). The median nonalcoholic fatty liver disease activity scores at the end of treatment were significantly lower in the BIB-treated compared with the sham-treated groups (2 [0.75] vs 4 [2.25]; P = .03). There was a trend toward improvement in the median steatosis scores (1 [0.75] vs 1 [1]; P = .075). There was no change in the median loblular inflammation, hepatocellular ballooning, or fibrosis scores in both groups after treatment. LIMITATIONS Pilot study with small numbers and short duration. CONCLUSION Results from this pilot study demonstrated that addition of BIB for 6 months provided a greater loss of BMI and improvement in 2 of 5 histologic parameters of nonalcoholic fatty liver disease. A longer study with larger numbers will be required to prove whether or not the therapy is meaningful in the treatment of NASH.

Experienced versus inexperienced confocal endoscopists in the diagnosis of gastric adenocarcinoma and intestinal metaplasia on confocal images

BACKGROUND Confocal laser endomicroscopy (CLE) may be used to diagnose gastric cancer and intestinal metaplasia, but the impact of CLE experience on the accuracy of confocal diagnosis of gastric cancer and intestinal metaplasia is not clear. OBJECTIVE To establish the sensitivity, specificity, and intragroup interobserver agreement of CLE image interpretation by 3 experienced (group 1) and 3 inexperienced (group 2) CLE endoscopists for diagnosing gastric intestinal metaplasia (GIM) and adenocarcinoma. DESIGN Blinded review of CLE images for the diagnosis of gastric cancer or intestinal metaplasia. SETTING Tertiary care hospital. PATIENTS CLE images obtained ex vivo from gastrectomy specimens with proven gastric cancer and CLE images obtained in vivo from Chinese subjects older than 50 years of age by using matched biopsy specimens as reference standards. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, and intragroup interobserver agreement of CLE image interpretation. RESULTS Interpretation of in vivo images by group 1 was associated with higher sensitivity (95.2% vs 61.9%, P = .039) and higher specificity (93.3% vs 62.2%, P < .001) for GIM than interpretation by group 2. The agreement between interpretation by group 1 and histology for GIM was higher than that for group 2 (κ = 0.864 vs 0.217). The sensitivity (93.3% for group 1 vs 86.7% for group 2, P = 1.000) and specificity (87.7% for group 1 vs 80.7% for group 2, P = .344) of interpretation of ex vivo CLE images for the diagnosis of gastric adenocarcinoma was similar for groups 1 and 2. LIMITATIONS Single-center study. CONCLUSIONS Experience in CLE was associated with greater accuracy in the diagnosis of intestinal metaplasia.

Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn's disease and ulcerative colitis

Background:Increased cell shedding with gap formation and local barrier dysfunction can be identified endomicroscopically in the terminal ileum of patients with inflammatory bowel disease. We aim to evaluate whether these changes are also present in the duodenum of patients with inflammatory bowel disease. Methods:Fifteen patients with Crohns disease (CD), 10 patients with ulcerative colitis (UC), and 10 controls underwent fluorescein-aided confocal laser endomicroscopy (CLE). CLE was performed on macroscopically normal antral and duodenal (D1, D2, D3, D4) mucosa. Representative CLE images were prospectively analyzed. Images were scored for the number of epithelial gaps, cell shedding, and the degree of fluorescein leakage into the intestinal lumen. Results:Both CD and UC patients had significantly more epithelial gaps, epithelial cell shedding, and leakage of fluorescein into the duodenal lumen than controls. The degree of cell shedding and epithelial gap formation was similar in CD and UC patients. In all cases, macroscopic endoscopic appearances of the duodenum were normal, and conventional histological analysis showed a mild nonspecific duodenitis in 7 of 15 patients with CD. Patients with UC had a histologically normal duodenum. Gap formation, cell shedding, and fluorescein leakage was similar in CD with active compared with inactive disease, except for D2 shedding. Conclusions:CLE can detect epithelial damage and barrier loss in the duodenum of CD and UC patients that is not apparent on conventional endoscopy or histology.

Roles of linear and circular polarization properties and effect of wavelength choice on differentiation between ex vivo normal and cancerous gastric samples

Abstract. Multispectral Mueller matrix imaging was performed over a spectral range from 470 to 632 nm on 4-μm unstained gastric tissue sections. A complete set of polarization parameters was derived. The combination of linear depolarization and linear retardance yields the highest accuracy in sample classification. When the depolarization of linearly polarized light due to scattering is independent of the orientation angle of the incident linear polarization vector, the derivation of linear polarization properties will require only 3×3 Mueller matrix, which would significantly reduce the complexity of the polarimetry imaging system. When additional parameters are needed to complement the two linear polarization parameters, retardance, circular depolarization, and depolarization can be included in classification in the order of preference. However, these additional parameters would require the measurement of 4×4 Mueller matrix. In addition, it appears that wavelength is not a critical factor in terms of classification accuracy for thin tissue sections in this study.

Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active Helicobacter pylori infection compared with histopathology (11%-27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intragenic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normal-like epigenomic patterns were associated with regression.

Current status on the diagnosis and management of pancreatic cysts in the Asia-Pacific region: role of endoscopic ultrasound.

Endoscopic ultrasound (EUS) and EUS‐guided fine‐needle aspiration (EUS‐FNA) play increasingly prominent roles in the diagnosis and management of pancreatic cysts. The Asian Consortium of Endoscopic Ultrasound was recently formed to conduct collaborative research in this area. This is a review of literature on true pancreatic cysts. Due to the lack of systematic studies, there are no robust data on the true incidence of pancreatic cystic lesions in Asia and any change in over the recent decades. Certain EUS morphological features have been used to predict particular types of pancreatic cysts. Pancreatic cyst fluid viscosity, cytology, pancreatic enzymes, and tumor markers, in particular carcinoembryonic antigen, can aid in the diagnosis of pancreatic cysts. Hemorrhage and infection are the most common complications of EUS‐FNA of pancreatic cysts. Pancreatic cysts can either be observed or resected depending on the benign or malignant nature, or malignant potential of the lesions. Guidelines from an international consensus did not require positive cytological findings to be present in their recommendation for resection, which included all mucinous cystic neoplasms, all main‐duct intraductal papillary mucinous neoplasms (IPMN), all mixed IPMN, symptomatic side‐branch IPMN, and side‐branch IPMN larger than 3 cm. In patients with poor surgical risks, EUS‐guided cyst ablation of mucinous pancreatic cysts is an alternative. As long‐term prospective data on pancreatic cysts are still not available in Asia, management strategies are largely based on risk stratification by surgical risk and malignant potential. Gene expression profiling of pancreatic cyst fluid and confocal laser endomicroscopic examination of pancreatic cysts are novel techniques currently being studied.

Investigation on the potential of Mueller matrix imaging for digital staining.

Digital staining based on Mueller matrix measurements and their derivatives was investigated. Mueller matrix imaging was performed at the microscopic level on gastric tissue sections. Full Mueller matrices (4 × 4) were reconstructed using recorded images, followed by the extraction of polarization parameters. The most effective parameters and their combinations were extracted from Mueller matrix elements, principal component scores and polarization parameters respectively to classify samples into three categories - i.e. cancer, dysplasia and intestinal metaplasia/normal glands for various regions of interest sizes. It was observed that two-step classification yielded higher classification accuracy than the traditional one-step classification and that pixel classification based on Mueller matrix elements yielded higher accuracy than that based on polarization parameters and derived principal components. Moreover, Mueller matrix images with a lower spatial resolution generated higher classification accuracy but those with a higher spatial resolution revealed more morphological details.ns. The original stained image (top) and the digital staining image (bottom).

Narrow-band imaging and white-light endoscopy with optical magnification in the diagnosis of dysplasia in Barrett’s esophagus: results of the Asia-Pacific Barrett’s Consortium

Objective: The advent and utility of new endoscopic imaging modalities for predicting the histology of Barrett’s esophagus (BE) in real time with high accuracy appear promising and could potentially obviate the need to perform random biopsies where guidelines are poorly adhered to. We embarked on evaluating the performance characteristics of white-light endoscopy with magnification (WLE-z), narrow-band imaging with magnification (NBI-z) and a combination of both modalities. Design: This was a prospective online study with 28 endoscopists from 11 countries (Asia-Pacific region) participating as assessors. In total, 35 patients with BE were assessed using 150 slides from WLE-z and NBI-z randomly arranged using a simple classification with corresponding histology. The overall Accuracy (Acc), Sensitivity (Sn), Specificity (Sp), Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of WLE-z, NBI-z and a combination of both were calculated. Results: The overall Acc for WLE-z and NBI-z images was 87.1 % and 88.7 %, respectively. When images from the two modalities were placed side by side, the Acc increased to 90.3 %. The Sn, Sp, PPV, and NPV of WLE-z were 48 %, 92 %, 45 %, and 93 % while with NBI-z, these improved to 89 %, 89 %, 56 %, and 98 %, respectively. When both imaging modalities were viewed together, they improved further to 93 %, 90 %, 61 %, and 99 %. Conclusion: The high NPV (99 %) when both WLE-z and NBI-z were used simultaneously indicates that areas with regular appearance that are diagnosed with confidence can effectively be left alone and not biopsied when performed at a skilled resourced center. This approach could potentially lead to a paradigm shift of how patients with BE are assessed.

Structured endoscopic ultrasonography (EUS) training program improved knowledge and skills of trainees: Results from the Asian EUS Group

A major reason impeding the growth of endoscopic ultrasound (EUS) in Asia is the lack of training availability. We aimed to prospectively evaluate the effectiveness of a short‐term structured EUS training program in improving the knowledge and skill of EUS among trainees.