Xianyong Gui

Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis

Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohns disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.

Colorectal glandular-neuroendocrine mixed tumor: pathologic spectrum and clinical implications.

Colorectal glandular-neuroendocrine mixed tumor is an uncommon entity with ill-defined clinicopathologic characteristics. We describe the clinicopathology of 23 new cases and review 67 previously reported cases. Clinically, patients (mean age, 61.9 y; male: female, 1.0:1.1) presented with a positive fecal occult blood test or visible rectal bleeding (44%), abdominal pain or change in bowel movement pattern (25%), bowel obstruction (19%), or weight loss (19%). Endoscopically, the tumors presented as a polypoid lesion (57%), a mass lesion (30%), or an ulcerating lesion (9%). Tumors were located in the right colon (56%), transverse colon (3%), and left colon (41%). Surgical resection was the treatment of choice in 83% of cases. After follow-up for an average of 20 months, the tumor-related death rate was 68%. Histologically, 42% were classified as composite tumors and 58% were classified as collision tumors. An adenoma to carcinoma, and then carcinoma to mixed tumor progression through the APC/&bgr;-catenin pathway was seen in a majority of cases. Both the glandular and the neuroendocrine components of the mixed tumor can show a spectrum of differentiation, and each component can metastasize separately regardless of its percentage volume. On the basis of the combined analysis of the pathologic spectrum and the clinical behavior of our series and previously reported cases, we propose a new classification system that reflects the differentiation of each component in colorectal glandular-neuroendocrine mixed tumor to facilitate uniform reporting and to better predict its clinical behavior.

Complete mucosal healing defined by endoscopic Mayo subscore still demonstrates abnormalities by novel high definition colonoscopy and refined histological gradings.

BACKGROUND AND STUDY AIMS A novel high definition colonoscopy imaging technique (i-Scan) can characterize, in detail, colonic mucosa in patients with ulcerative colitis, and may provide additional information about mucosal healing. The aim of this study was to create a more refined histological and endoscopic criteria based on this novel technique in order to redefine inflammatory activity and mucosal healing. PATIENTS AND METHODS A total of 78 patients with ulcerative colitis were assessed by high definition colonoscopy as well as by white light endoscopy (WLE). Mayo endoscopic subscores were assigned to patients according to WLE findings. Mucosal and vascular patterns on high definition colonoscopy were each graded from 1 - 4. A histological scoring system (ECAP system) was designed to reflect all histological changes in ulcerative colitis. RESULTS The overall high definition imaging scores (mucosal and vascular patterns) were significantly correlated with Mayo endoscopic subscores (rs = 0.86, 95 % confidence interval [CI] 0.79 - 0.91; P < 0.0001). Of those with Mayo endoscopic subscore of 0, 30.4 % had an abnormal mucosal pattern and 73.9 % of them had an abnormal vascular pattern on high definition colonoscopy; a score of 6 or less had a sensitivity of 95.8 % (95 %CI 85.7 % - 99.3 %) and specificity of 75.9 % (95 %CI 56.5 % - 90.0 %) to detect mucosal healing as defined by Mayo endoscopy subscore of 0 or 1. Furthermore, mucosal and vascular pattern scores were also significantly correlated with most parameters of the proposed ECAP score. CONCLUSION The subtle histological abnormalities underlying the apparently healed mucosa in ulcerative colitis could be detected using high definition colonoscopy and the refined ECAP histology scoring system. These techniques detect residual abnormalities in the majority of patients with seemingly complete mucosal healing by conventional Mayo criteria.

Ultrasound Shear Wave Elastography and Contrast Enhancement: Effective Biomarkers in Crohn's Disease Strictures

Background: Inflammation, fibrosis, and muscular hypertrophy lead to thickened bowel in Crohns disease forming strictures. Ultrasound shear wave elastography (SWE) measures bowel wall stiffness. Contrast-enhanced ultrasound (CEUS) uniquely detects bowel wall inflammation. We aim to correlate SWE of ileal Crohns disease in vivo to CEUS peak enhancement and pathology grades of inflammation, fibrosis, and muscular hypertrophy. Methods: In a prospective institutional review board–approved study, 105 consecutive ileal patients with Crohns disease received ultrasound. At maximal bowel wall thickness (>4 mm), SWE and CEUS were performed. Fifteen patients had ileal resection within a mean time interval of 71.0 ± 66.9 days. Pathology scores for inflammation, fibrosis, and muscular hypertrophy were compared with SWE and CEUS measurements. Results: Mean in vivo SWE velocity for patients with and without surgery was 2.8 ± 0.7 and 2.2 ± 0.8 m/s (P < 0.01), respectively. In all ileal specimens, chronic exceeded active inflammatory change (P < 0.001). There was an inverse relationship between CEUS peak enhancement and both fibrosis, r = −0.59, P = 0.02, and SWE velocity measurements, r = −0.61, P = 0.03. Strictured bowel specimens had more smooth muscle hypertrophy than fibrosis, P < 0.001. There was moderate correlation between SWE and muscular hypertrophy, r = 0.59, P = 0.02 and no significant relationship between SWE and fibrosis scores (P > 0.05). Conclusions: Stiffer bowel from smooth muscle hypertrophy increases SWE measurements. We report a novel relation of high SWE with muscle hypertrophy, and inverse relationship with CEUS peak enhancement; providing differentiation between active and chronic bowel wall inflammation to improve selection between medical therapy and surgery.

Serrated Adenoma Prevalence in Inflammatory Bowel Disease Surveillance Colonoscopy, And Characteristics Revealed by Chromoendoscopy and Virtual Chromoendoscopy

BACKGROUND Sessile or nonpolypoid neoplastic lesions, including sessile serrated adenomas (SSAs), are difficult to detect in patients with inflammatory bowel disease (IBD). OBJECTIVES To assess the prevalence and endoscopic features of SSA in IBD patients undergoing surveillance colonoscopy using novel endoscopic techniques. METHODS Histology results of biopsies from a cohort of 87 patients (47 men; median age 51.4 years; median duration of disease 16.9 years; ulcerative colitis [n=40], Crohn disease [n=43], ischemic colitis [n=4]) with longstanding colonic IBD undergoing surveillance colonoscopy were reviewed. Lesions of dysplasia (adenoma-like mass, or dysplasia-associated lesion or mass), SSAs, adenoma-like polyps, hyperplastic polyps and inflammatory polyps were identified. Surveillance colonoscopy using high-definition alone, or with iScan (Pentax, USA) dye-sprayed or virtual chromoendoscopy was performed. Lesion characteristics were described before histological diagnosis. RESULTS Fourteen SSAs were detected in 87 (11%) IBD patients. The endoscopic characteristics of SSA lesions were: nonpolypoid appearance (86%), predominant localization in the proximal colon (79%), >6 mm in size (79%), cloudy cover (64%), Kudo pit pattern modified type IIO (86%) and irregular spiral vascular pattern (79%). Among the 44 SSAs and hyperplastic polyps found in the present study, the above characteristics of SSA at colonoscopy had a sensitivity of 92.86% (95% CI 66.06% to 98.8%) and specificity of 93.33% (95% CI 77.89% to 98.99%) in predicting a histological diagnosis of SSA (positive predictive value 86.67%, negative predictive value 96.55%). CONCLUSION SSAs are a common finding at surveillance colonoscopy in IBD and have several characteristic features. Further studies are needed to evaluate the natural history of these lesions in IBD patients.

Smooth Muscle Hyperplasia/Hypertrophy is the Most Prominent Histological Change in Crohn’s Fibrostenosing Bowel Strictures: A Semiquantitative Analysis by Using a Novel Histological Grading Scheme

Background: The simplistically and ambiguously termed ‘fibrostenosis’ of bowel is a hallmark of severe Crohn’s disease [CD] and a major contributor to medical treatment failure. Non-invasive imaging assessment and novel medical therapy targeting this condition are under investigation, which particularly requires a better understanding of the underlying histological basis. Methods: We analysed 48 patients with stricturing Crohn’s ileitis or/and colitis that required surgical resection. The most representative sections of the fibrostenotic, non-stenotic and uninvolved regions were reviewed for histological analysis. For each layer of bowel wall (mucosa including muscularis mucosae [MU], submucosa [SM], muscularis propria [MP], subserosal adventitia [SS]), histological abnormalities were evaluated individually, including active and chronic inflammation, fibrosis, smooth muscle hyperplasia or hypertrophy, neuronal hypertrophy and adipocyte proliferation. A novel semiquantitative histological grading scheme was created. Results: The most significant histopathological features characterizing the stricturing intestines were smooth muscle hyperplasia of SM, hypertrophy of MP and chronic inflammation. The muscular alteration was predominant in all layers. The overall muscular hyperplasia/hypertrophy was positively correlated with chronic inflammation and negatively correlated with fibrosis, whereas SM muscular hyperplasia was also associated with MU active inflammation. Similar changes, to a lesser extent, occurred in the adjacent non-stenotic inflamed bowel as well. Conclusions: In CD-associated ‘fibrostenosis’, it is the smooth muscle hyperplasia/hypertrophy that contributes most to the stricturing phenotype, whereas fibrosis is less significant. The ‘inflammation-smooth muscle hyperplasia axis’ may be the most important in the pathogenesis of Crohn’s strictures.

A Randomized Trial Comparing High Definition Colonoscopy Alone With High Definition Dye Spraying and Electronic Virtual Chromoendoscopy for Detection of Colonic Neoplastic Lesions During IBD Surveillance Colonoscopy

Objectives:Dye spraying chromoendoscopy (DCE) is recommended for the detection of colonic neoplastic lesions in inflammatory bowel disease (IBD). The majority of neoplastic lesions are visible endoscopically and therefore targeted biopsies are appropriate for surveillance colonoscopy. To compare three different techniques for surveillance colonoscopy to detect colonic neoplastic lesions in IBD patients: high definition (HD), (DCE), or virtual chromoendoscopy (VCE) using iSCAN image enhanced colonoscopy.Methods:A randomized non-inferiority trial was conducted to determine the detection rates of neoplastic lesions in IBD patients with longstanding colitis. Patients with inactive disease were enrolled into three arms of the study. Endoscopic neoplastic lesions were classified by the Paris classification and Kudo pit pattern, then histologically classified by the Vienna classification.Results:A total of 270 patients (55% men; age range 20–77 years, median age 49 years) were assessed by HD (n=90), VCE (n=90), or DCE (n=90). Neoplastic lesion detection rates in the VCE arm was non-inferior to the DCE arm. HD was non-inferior to either DCE or VCE for detection of all neoplastic lesions. In the lesions detected, location at right colon and the Kudo pit pattern were predictive of neoplastic lesions (OR 6.52 (1.98–22.5 and OR 21.50 (8.65–60.10), respectively).Conclusions:In this randomized trial, VCE or HD-WLE is not inferior to dye spraying colonoscopy for detection of colonic neoplastic lesions during surveillance colonoscopy. In fact, in this study HD-WLE alone was sufficient for detection of dysplasia, adenocarcinoma or all neoplastic lesions.

Sa1754 Distinctive Th17 Lymphocyte Plasticity in Intestinal Lamina Propria of IBD Patients Compared With Healthy Controls

Interleukin-6 Drives Production of Pathogenic Cytokines by Innate Lymphoid Cells in Patients and Mice With Chronic Intestinal Inflammation Nick Powell, Jonathan W. Lo, Paolo Biancheri, Anna Vossenkamper, Eirini D. Pantazi, Emilie Stolarczyk, Alan Walker, Paul Scott, James B. Canavan, Esperanza Perucha, Natividad Garrido-Mesa, Ian Jackson, Francesca Ammoscato, Peter M. Irving, Jeremy D. Sanderson, Bu Hayee, Julian Parkhill, MacDonald Thomas, Graham M. Lord

Recent Advances in the Recognition and Management of Eosinophilic Esophagitis

The incidence and recognition of eosinophilic esophagitis is increasing. Pathophysiological understanding of eosinophilic esophagitis is improving and an immunological reaction to ingested food is likely to play a significant role. Patients present with dysphagia and food bolus obstruction. Both histological and endoscopic criteria have been developed and validated. Dietary therapy, topical steroid therapy, proton pump inhibitors and endoscopic dilation are the main approaches to therapy; however, novel targeted therapies are being developed. Among the food items commonly implicated are wheat, dairy, nuts, soy, shellfish and eggs. A multidisciplinary approach to management in dedicated clinics may yield the best results.

Is Pneumatosis Cystoides Intestinalis Gas-Distended and Ruptured Lymphatics?: Reappraisal by Immunohistochemistry

CONTEXT Pneumatosis cystoides intestinalis (PCI) is a condition with multiple gas-filled cysts within the bowel wall, associated with diverse background diseases. Its pathogenesis is still a mystery. Some previous observations scattered in the literature have suggested an association of the cystic spaces in PCI with the lymphatics. OBJECTIVE To further investigate whether PCI results from the ballooning of gas-filled lymphatic channels. DESIGN We did immunostaining of podoplanin, a mucoprotein preferentially expressed in lymphatic endothelial cells, in 13 cases (8 men, 5 women; age range, 18-80 years) of PCI. Ten cases were diagnosed in resected segments of bowel and 3 in biopsies. Pneumatosis was seen in the right side of the colon (9 cases), transverse colon (1 case), sigmoid colon (1 case), and small bowel (2 cases). In addition, immunostaining for CD31, calretinin, WT1, CD68, smooth muscle actin, desmin, vimentin, and cytokeratins was also performed for comparison and correlation. RESULTS A strong immunopositivity of podoplanin was seen in a condensed linear structure in the pericystic interstitium in 100% of the cases, but was not seen in the overlying giant and flat cells that were all CD68-positive histiocytes. Meanwhile, the podoplanin-expressing structure was negative for calretinin and WT1, which ruled out the possible mesothelial origin. There were coexistent variable immunopositivity of smooth muscle actin, which suggests an admixture of myofibroblasts. These findings indicated that the PCI cases were gas-distended lymphatics with the lymphatic epithelium ruptured and embedded in the reactive histiocytes and giant cells. CONCLUSION Our findings support the lymphatic theory about the pathogenesis of PCI.