Alan C. Moss

Impact of Antibodies to Infliximab on Clinical Outcomes and Serum Infliximab Levels in Patients With Inflammatory Bowel Disease (IBD): A Meta-Analysis

OBJECTIVES:Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients’ ATI status.METHODS:MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies. Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.RESULTS:Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95% confidence interval (CI): 2.0–4.9, P<0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N=494) with Crohns disease (RR: 3.2, 95% CI: 1.9–5.5, P<0.0001). Data only from patients with ulcerative colitis (n=86) exhibited a non-significant RR of loss of response of 2.2 (95% CI: 0.5–9.0, P=0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n=243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was −0.8 (95% CI −1.2, −0.4, P<0.0001). A funnel plot suggested the presence of publication bias.CONCLUSIONS:The presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.

Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander?

&NA; The role of cytomegalovirus (CMV) in exacerbations of inflammatory bowel disease (IBD) remains a topic of ongoing debate. Current data are conflicting as to whether CMV worsens inflammation in those with severe colitis, or is merely a surrogate marker for severe disease. The interpretation of existing results is limited by mostly small, retrospective studies, with varying definitions of disease severity and CMV disease. CMV colitis is rare in patients with Crohns disease or mild‐moderate ulcerative colitis. In patients with severe and/or steroid‐refractory ulcerative colitis, local reactivation of CMV can be detected in actively inflamed colonic tissue in about 30% of cases. Where comparisons between CMV+ and CMV− steroid‐refractory patients can be made, most, but not all, studies show no difference in outcomes according to CMV status. Treatment with antiviral therapy has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies. This article reviews the immunobiology of CMV disease, the evidence for CMVs role in disease severity, and discusses the outcomes with antiviral therapy. (Inflamm Bowel Dis 2010)

Endoscopic Resection for Barrett's High-Grade Dysplasia and Early Esophageal Adenocarcinoma: An Essential Staging Procedure With Long-Term Therapeutic Benefit

OBJECTIVES: Patients with Barretts high‐grade dysplasia (HGD) or early esophageal adenocarcinoma (EAC) that is shown on biopsy alone continue to undergo esophagectomy without more definitive histological staging. Endoscopic resection (ER) may provide more accurate histological grading and local tumor (T) staging, definitive therapy, and complete Barretts excision (CBE); however, long‐term outcome data are limited. Our objective was to demonstrate the effect on histological grade or local T stage, efficacy, safety and long‐term outcome of ER for Barretts HGD/EAC and of CBE in suitable patients. METHODS: This prospective study at two Australian academic hospitals involved 75 consecutive patients over 7 years undergoing ER for biopsy‐proven HGD or EAC, using multiband mucosectomy or cap technique. In addition, CBE by 2–3‐stage radical mucosectomy was attempted for all Barretts segments ≤3 cm in length in patients aged <75 years with minimal comorbidities. RESULTS: Biopsy histology showed HGD in 89% of patients and EAC in 11%. However, ER histology resulted in altered grading or staging in 48% of patients (down 28%, up 20%), with HGD in 53%, low‐grade dysplasia (LGD) in 19%, mucosal adenocarcinoma in 13%, submucosal adenocarcinoma in 9%, and no dysplasia in 4% of patients. The CBE success rate was 94%. Complications were one aspiration (hospitalization with full recovery) and six strictures successfully dilated endoscopically. During the mean follow‐up of 31 months (range 3–89), there was no recurrence at ER sites, 11% developed metachronous lesions and five patients underwent esophagectomy for ER‐demonstrated submucosal invasion. Esophagectomy specimens were T0N0M0 in three and T1N0M0 in two patients. There were no deaths due to adenocarcinoma. CONCLUSIONS: ER alters histological grade or local T stage in 48% of patients and dramatically reduces esophagectomy rates by providing safe and effective therapy. ER has a high success rate (94%) for CBE in short segment Barretts esophagus.

Large refractory colonic polyps: is it time to change our practice? A prospective study of the clinical and economic impact of a tertiary referral colonic mucosal resection and polypectomy service (with videos)

BACKGROUND Patients who have large, difficult, colorectal lesions not readily amenable to endoscopic resection are often referred directly to surgery. The application of advanced polypectomy and endoscopic mucosal resection (EMR) techniques undertaken by a tertiary referral colonic mucosal resection and polypectomy service (TRCPS) is not often considered but may be superior to surgery. OBJECTIVE To evaluate the safety, efficacy, and cost savings of a TRCPS for colorectal lesions. DESIGN Prospective intention-to-treat analysis. SETTING Tertiary academic referral center. PATIENTS In a 21-month period ending in April 2008, consecutive patients with large or complex colorectal polyps referred by other specialist endoscopists were prospectively enrolled on an intention-to-treat basis. INTERVENTION For sessile lesions, a standardized EMR approach was used. Pedunculated lesions were removed with or without pretreatment with an Endoloop procedure. MAIN OUTCOME MEASUREMENTS Complete resection, complications, recurrence, and potential cost savings comparing actual outcome of the cohort with a hypothetical analysis of surgical management. RESULTS This study included 174 patients (mean age 68 years) who were referred with 193 difficult polyps (186 laterally spreading, mean size 30 mm [range 10-80 mm]). We totally excised 173 laterally spreading lesions by EMR (115 piecemeal, 58 en bloc). Invasive adenocarcinoma was found in 6 lesions-5 treated successfully with EMR. Eleven patients were referred directly to surgery without an endoscopic attempt due to suspected invasive carcinoma. Seven >30-mm, pedunculated polyps were removed. There were no perforations. A total of 20 bed days was used because of endoscopic complications. Among all patients referred, 90% avoided the need for surgery. Excluding patients who were treated surgically for invasive cancer, the procedural success was 95% (157 of 168). By using Australian cost estimates applied to the entire group and compared with cost estimates assuming all patients had undergone surgery, we calculated the total medical cost savings was

Do the benefits of metal stents justify the costs? A systematic review and meta-analysis of trials comparing endoscopic stents for malignant biliary obstruction.

6990 (U.S.) per patient, or a total savings of

Factors that predict bleeding following endoscopic mucosal resection of large colonic lesions.

1,216,231 (U.S.). LIMITATION Not a randomized trial. CONCLUSIONS Colonoscopic polypectomy performed by a TRCPS on large or difficult polyps is technically effective and safe. This approach results in major cost savings and avoids the potential complications of colonic surgery. This type of clinical pathway should be developed to enhance patient outcomes and reduce health care costs.

The target sign: an endoscopic marker for the resection of the muscularis propria and potential perforation during colonic endoscopic mucosal resection

Background A variety of stent designs has been studied for endoscopic stenting of the bile duct in patients with malignant biliary obstruction. Although metal stents are associated with longer patency, their costs are significantly higher than plastic stents. Aims To compare clinical outcome and cost-effectiveness of endoscopic metal and plastic stents for malignant biliary obstruction by a systematic review and meta-analysis of all randomized controlled trials in this area. Methods We conducted searches to identify all randomized controlled trials in any language from 1966 to 2006 using electronic databases and hand-searching of conference abstracts. Meta-analysis was performed with RevMan software [Review Manager (RevMan) version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003]. Results Seven randomized controlled trials were identified that met the inclusion criteria, and 724 participants were randomized to either metal or plastic endoscopic stents. No significant difference between the two stent types in terms of technical success, therapeutic success, 30-day mortality or complications was observed. Metal stents were associated with a significantly less relative risk (RR) of stent occlusion at 4 months than plastic stents [RR, 0.44; 95% confidence interval (CI) 0.3, 0.63; P<0.01]. The overall risk of recurrent biliary obstruction was also significantly lower in patients treated with metal stents (RR, 0.52; 95% confidence interval 0.39, 0.69; P<0.01). The median incremental cost-effectiveness ratio of metal stents was

Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study.

1820 per endoscopic retrograde cholangiopancreatography prevented. Conclusion Endoscopic metal stents for malignant biliary obstruction are associated with significantly higher patency rates than plastic stents as early as 4 months after insertion. Metal stents will be cost-effective if the unit cost of additional endoscopic retrograde cholangiopancreatographies per patient exceeds

A Randomized, Double-Blind Trial of Succinylated Gelatin Submucosal Injection for Endoscopic Resection of Large Sessile Polyps of the Colon

1820.

Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses.

BACKGROUND AND STUDY AIMS Endoscopic mucosal resection (EMR) for large colonic laterally spreading tumors (LSTs) is a safe, efficacious, and cost-effective treatment. The most common serious complication is delayed bleeding, which reduces these advantages, but consensus guidelines for large-polyp EMR do not exist. PATIENTS AND METHODS Data from two large prospective intention-to-treat studies of EMR for colonic LSTs 20 mm or greater in size were analyzed. Data collection was comprehensive, and included patient and lesion characteristics. EMR technique and cessation of anticoagulant and antiplatelet therapy was standardized. Clinically significant delayed bleeding was defined as that requiring hospital admission. RESULTS EMR was performed on 302 lesions in 288 patients. There was clinically significant delayed bleeding in 21 cases (7 %). Ten underwent colonoscopy. One required angiography. One required surgery after perforation following hemostatic clip placement. There were no deaths. Risk factors for bleeding on multivariate analysis were right colon location [adjusted odds ratio (OR) 4.4, P = 0.01], use of aspirin (OR 6.3, P = 0.005), and age (OR per decade of age 1.70). All bleeds occurred before aspirin was restarted. Patient characteristics, including ASA grade and co-morbidity type, were not predictive. Despite requiring more complex EMR, larger lesion size ( P = 0.2), multiple excisions rather than en bloc resection ( P = 0.1), polyp morphology ( P = 0.2), and previous attempts ( P = 0.5), were not associated with increased risk. CONCLUSIONS Proximal lesion location is a highly significant risk for clinically significant delayed bleeding following colonic EMR, and this knowledge could form the basis of a targeted therapeutic trial. Recent aspirin use also increases bleeding risk--specific consensus guidelines in this area are required for colonic EMR.