Bu Hayee

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

Systematic review: bile acids and intestinal inflammation-luminal aggressors or regulators of mucosal defence?

Inflammatory bowel diseases (IBD), comprising Crohns disease and ulcerative colitis (UC), are chronic conditions attributed to an aberrant immune response to luminal triggers. Recently, published work suggests a pathogenic role for bile acids in this context.

Magnification narrow-band imaging for the diagnosis of early gastric cancer: a review of the Japanese literature for the Western endoscopist

With advances in endoscopic imaging and image enhancement, it is now possible to reliably differentiate non-neoplastic pathology from cancer throughout the GI tract. Techniques developed and reported in the Japanese literature provide a wealth of information that is not immediately accessible or easy to interpret. Despite this, along with many other challenges facing the “Western” endoscopist, much of this experience can be translated and summarized in a diagnostic algorithm. In this review, we collate the Japanese data on the use of magnifying endoscopy and narrow-band imaging in the stomach.

Gastroesophageal reflux after peroral endoscopic myotomy: a multicenter case–control study

Background and study aims The variables associated with gastroesophageal reflux (GER) after peroral endoscopic myotomy (POEM) are largely unknown. This study aimed to: 1) identify the prevalence of reflux esophagitis and asymptomatic GER in patients who underwent POEM, and 2) evaluate patient and intraprocedural variables associated with post-POEM GER. Patients and methods All patients who underwent POEM and subsequent objective testing for GER (pH study with or without upper gastrointestinal [GI] endoscopy) at seven tertiary academic centers (one Asian, two US, four European) were included. Patients were divided into two groups: 1) DeMeester score ≥ 14.72 (cases) and 2) DeMeester score of < 14.72 (controls). Asymptomatic GER was defined as a patient with a DeMeester score ≥ 14.72 who was not consuming proton pump inhibitor (PPI). Results A total of 282 patients (female 48.2 %, Caucasian 84.8 %; mean body mass index 24.1 kg/m2) were included. Clinical success was achieved in 94.3 % of patients. GER evaluation was completed after a median follow-up of 12 months (interquartile range 10 - 24 months). A DeMeester score of ≥ 14.72 was seen in 57.8 % of patients. Multivariable analysis revealed female sex to be the only independent association (odds ratio 1.69, 95 % confidence interval 1.04 - 2.74) with post-POEM GER. No intraprocedural variables were associated with GER. Upper GI endoscopy was available in 233 patients, 54 (23.2 %) of whom were noted to have reflux esophagitis (majority Los Angeles Grade A or B). GER was asymptomatic in 60.1 %. Conclusion Post-POEM GER was seen in the majority of patients. No intraprocedural variables were identified to allow for potential alteration in procedural technique.

Efficacy and Safety of Peroral Endoscopic Myotomy for Treatment of Achalasia After Failed Heller Myotomy

BACKGROUND & AIMS: In patients with persistent symptoms after Heller myotomy (HM), treatment options include repeat HM, pneumatic dilation, or peroral endoscopic myotomy (POEM). We evaluated the efficacy and safety of POEM in patients with achalasia with prior HM vs without prior HM. METHODS: We conducted a retrospective cohort study of 180 patients with achalasia who underwent POEM at 13 tertiary centers worldwide, from December 2009 through September 2015. Patients were divided into 2 groups: those with prior HM (HM group, exposure; n = 90) and those without prior HM (non‐HM group; n = 90). Clinical response was defined by a decrease in Eckardt scores to 3 or less. Adverse events were graded according to criteria set by the American Society for Gastrointestinal Endoscopy. Technical success, clinical success, and rates of adverse events were compared between groups. Patients were followed up for a median of 8.5 months. RESULTS: POEM was technically successful in 98% of patients in the HM group and in 100% of patients in the non‐HM group (P = .49). A significantly lower proportion of patients in the HM group had a clinical response to POEM (81%) than in the non‐HM group (94%; P = .01). There were no significant differences in rates of adverse events between the groups (8% in the HM group vs 13% in the non‐HM group; P = .23). Symptomatic reflux and reflux esophagitis after POEM were comparable between groups. CONCLUSIONS: POEM is safe and effective for patients with achalasia who were not treated successfully by prior HM. Although the rate of clinical success in patients with prior HM is lower than in those without prior HM, the safety profile of POEM is comparable between groups.

Comprehensive Analysis of Adverse Events Associated with per Oral Endoscopic Myotomy in 1826 Patients: An International Multicenter Study

Objectives:The safety of peroral endoscopic myotomy (POEM) is still debated since comprehensive analysis of adverse events (AEs) associated with the procedure in large multicenter cohort studies has not been performed. To study (1) the prevalence of AEs and (2) factors associated with occurrence of AEs in patients undergoing POEM.Methods:Patients who underwent POEM at 12 tertiary-care centers between 2009 and 2015 were included in this case–control study. Cases were defined by the occurrence of any AE related to the POEM procedure. Control patients were selected for each AE case by matching for age, gender, and disease classification (achalasia type I and II vs. type III/spastic esophageal disorders).Results:A total of 1,826 patients underwent POEM. Overall, 156 AEs occurred in 137 patients (7.5%). A total of 51 (2.8%) inadvertent mucosotomies occurred. Mild, moderate, and severe AEs had a frequency of 116 (6.4%), 31 (1.7%), and 9 (0.5%), respectively. Multivariate analysis demonstrated that sigmoid-type esophagus (odds ratio (OR) 2.28, P=0.05), endoscopist experience <20 cases (OR 1.98, P=0.04), use of a triangular tip knife (OR 3.22, P=0.05), and use of an electrosurgical current different than spray coagulation (OR 3.09, P=0.02) were significantly associated with the occurrence of AEs.Conclusions:This large study comprehensively assessed the safety of POEM and highly suggests POEM as a relatively safe procedure when performed by experts at tertiary centers with an overall 7.5% prevalence of AEs. Severe AEs are rare. Sigmoid-type esophagus, endoscopist experience, type of knife, and current used can be considered as predictive factors of AE occurrence.

Remission and relapse of Crohn’s disease following autologous haematopoietic stem cell transplantation for non-Hodgkin’s lymphoma

Autologous haematopoietic stem cell transplantation (HSCT) for Crohn’s disease has been described by Oyama and co-workers as producing remission in 11 of 12 patients with refractory Crohn’s disease after a median follow up of 18.5 months.1 They postulated that autologous HSCT was useful for refractory Crohn’s disease. We report the case of a 32 year old woman with biopsy proven Crohn’s disease diagnosed when she was 16 years old. Her mother also suffered from Crohn’s disease. She developed a KI1 positive anaplastic non-Hodgkin’s lymphoma (NHL) three years later, treated successfully with ablative CHOP chemotherapy and autologous HSCT, inducing remission for …

Utility of intrapapillary capillary loops seen on magnifying narrow-band imaging in estimating invasive depth of esophageal squamous cell carcinoma

BACKGROUND AND STUDY AIMS Intrapapillary capillary loops (IPCLs) have been used to estimate histopathological atypia and the invasion depth of squamous cell carcinoma (SCC). The aim of this study was to evaluate the clinical significance of IPCLs. PATIENTS AND METHODS A total of 358 consecutive patients with esophageal neoplasia on magnifying narrow-band imaging (M-NBI) were studied. The lesions were categorized according to the IPCL classification of Inoue et al. and were subsequently resected. Resected specimens were histopathologically analyzed to determine the invasion depth. The inter- and intraobserver agreements in the interpretation of IPCL images were also investigated. RESULTS A total of 446 lesions were diagnosed on M-NBI as IPCL type V lesions, which were further classified as 185 IPCL type V1, 109 type V2, 104 type V3, and 48 type Vn. Sensitivity and specificity of IPCL type V1-2 for invasion confined to the epithelium or lamina propria mucosa (m1-2) were 89.5 % (95 % confidence interval [CI] 85.4 % - 92.7 %) and 79.6 % (95 %CI 72.3 % - 85.7 %), respectively. Sensitivity and specificity of IPCL type V3 for invasion confined to the muscularis mucosa or slight submucosal invasion (m3-sm1) were 58.7 % and 83.8 %, respectively. Sensitivity and specificity of IPCL type Vn for deeper invasion (sm2-3) were 55.8 % and 98.6 %, respectively. Interobserver agreement was substantial (κ = 0.609, 0.641, and 0.705), as was intraobserver agreement (κ = 0.705 and κ = 0.819). CONCLUSION Changes in the morphology of IPCLs on M-NBI correlated with the depth of SCC invasion, and results were reproducible and reliable among observers. Identification of IPCL type V1-2 proved useful for the intraprocedural identification of m1-2 lesions, which are considered an absolute indication for endoscopic resection.

An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment

Summary Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability.

Golimumab: early experience and medium-term outcomes from two UK tertiary IBD centres

Objective To gain an understanding of the effectiveness of golimumab in a ‘real-world’ setting. Design Retrospective cohort study using prospectively maintained clinical records. Setting Two UK tertiary IBD centres. Patients Patients with ulcerative colitis (UC) were given golimumab at Guy’s & St Thomas and King’s College Hospitals between September 2014 and December 2016. Intervention Golimumab, a subcutaneously administered antitumour necrosis factor agent. Main outcome measures Clinical disease activity was assessed at baseline and at the first clinical review following induction therapy using the Simple Clinical Colitis Activity Index (SCCAI). Response was defined as an SCCAI reduction of 3 points or more. Remission was defined as an SCCAI of less than 3. Results Fifty-seven patients with UC completed golimumab induction therapy. Paired preinduction and postinduction SCCAI values were available for 31 patients and fell significantly from 7 (2–19) to 3 (0–11) (p<0.001). To these 31, an additional 13 patients who did not have paired SCCAI data but stopped treatment due to documented ‘non-response’ in the opinion of their supervising clinician, were added. Among this combined cohort, 23/44 (52%) had a clinical response, 15/44 (34%) achieved remission and 13/44 (30%) achieved corticosteroid-free remission. Faecal calprotectin and CRP fell (FC: pre-induction: 1096 (15-4800) μg/g, post-induction: 114 (11-4800) μg/g, p = 0.011; n = 20; CRP: pre-induction: 4 (1-59) mg/L, post-induction: 2 (1-34) mg/L, p = 0.01 for n = 43). Post-induction endoscopy was carried out in 23 patients and a mucosal healing (Mayo 0 or 1) rate of 35% was observed. Conclusions Our experience mirrors previously reported real-world cohorts and demonstrates similar outcomes to those observed in randomised controlled trials. These data demonstrate a meaningful reduction in clinical, biochemical and endoscopic disease activity as well as a steroid-sparing effect in patients with previously refractory disease.