Robert Richards

Diagnostic Yield of Spiral Enteroscopy When Performed for the Evaluation of Abnormal Capsule Endoscopy Findings

Background Spiral enteroscopy (SE) has emerged as a new alternative for deep intubation of the small intestine. SE is most often used to evaluate abnormal findings on capsule endoscopy (CE). Objective Investigate the ability of SE to reproduce abnormal findings detected on preceding CE. Design Prospective study. Setting Two academic tertiary care centers. Patients Consecutive patients undergoing SE to investigate a clinically significant finding on CE. Main Outcome Measurement Ability of SE to identify findings on CE. Results Total of 56 anterograde SE procedures were performed. CE findings included arteriovenous malformations (AVMs) (n=26), masses (n=8), ulcers (n=4), polyps (n=4), abnormal mucosa (n=6), fresh blood (n=6), and stricture (n=1). Majority of the patients had CE findings located in the jejunum (41 of 56 or 73.2%). Mean depth of enteroscope insertion was 224.6±68.7 cm. SE detected relevant small bowel pathology in 32 of 56 (57.1%) patients. Findings on CE were reproduced in 30 of 56 (53.6%) cases. Reproducibility was independent of patient body mass index (P=0.38), CE indication (P=0.24), CE lesion location (P=0.29), days between CE and SE (P=0.30), and depth of insertion (P=0.81). Type of CE findings (particularly AVMs) significantly affected SE reproducibility (P=0.015). SE procedure time was inversely related to SE reproducibility (odds ratio=0.94, 95% confidence interval=0.88-0.99, P=0.02). Limitations Small sample size and potential for false-positive CE study. Conclusions SE seems to be moderately effective (57.1%) in terms of its ability to locate pathology within the small intestine. The type of small bowel pathology targeted by SE may affect its clinical utility. AVMs observed on CE can be seen at the time of SE in the majority of cases (60%).

Can the blood urea nitrogen/creatinine ratio distinguish upper from lower gastrointestinal bleeding ?

We wanted to know if the blood urea nitrogen to creatinine (BUN/Cr) ratio could help distinguish upper from lower gastrointestinal bleeding. We analyzed retrospectively patients admitted to our hospital for gastrointestinal bleeding over the past 5 years. A total of 126 patients represented 74 upper bleeds and 52 lower bleeds. The mean BUN/Cr ratio was significantly higher in upper than lower bleeders, 34.8 and 17.8 respectively (p > 0.001). No lower bleeder had a ratio of ≥ 36, whereas 38% of upper bleeders had a ratio of ≥ 36. The BUN/Cr ratio may be an easy, cheap method of distinguishing upper from lower gastrointestinal bleeding in some cases. A BUN/Cr ratio of ≥ 36 suggests upper gastrointestinal bleeding, whereas a ratio of >36 is not helpful in locating the source of bleeding.

Toxic megacolon associated Clostridium difficile colitis

Toxic megacolon is a severe complication of Clostridium difficile (C. difficile) colitis. As the prevalence of C. difficile colitis increases and treatments become more refractory, clinicians will encounter more patients with C. difficile associated toxic megacolon in the future. Here, we review a case of toxic megacolon secondary to C. difficile colitis and review the current literature on diagnosis and management. We identify both clinical and radiologic criteria for diagnosis and discuss both medical and surgical options for management. Ultimately, we recommend using the Jalen criteria in conjunction with daily abdominal radiographs to help establish the diagnosis of toxic megacolon and to make appropriate treatment recommendations. Aggressive medical management using supportive measures and antibiotics should remain the mainstay of treatment. Surgical intervention should be considered if the patient does not clinically improve within 2-3 d of initial treatment.

MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis.

Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10 by RT-PCR; prostaglandin E2 (PGE2), cytoplasmic phospholipase A2 (cPLA2) and myeloperoxidase by immunoassay; and COX-2 and NF- κB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A2; reduced significantly the induced levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-κB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE2 in the colon and PGE2 metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-κB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-κB. MC-12 merits further development as an agent for the control of IBD.

Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen

Esterase hydrolysis of drugs can accelerate their elimination, thereby limiting their efficacy. Polyethylene glycol (PEG) covalently attached to drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), we examined whether pegylation of PI could abrogate its hydrolytic degradation by esterases; PI, known to inhibit colon cancer growth, has a carboxylic ester hydrolyzable by carboxylesterases (CES). We covalently attached mPEG-2000 to PI (PI-PEG) and studied its stability by exposing it to cells overexpressing CES and by administering it to mice. We also evaluated PI-PEG’s anticancer efficacy in human colon cancer xenografts and in Apcmin/+ mice. PI-PEG was stable in the presence of cells overexpressing CES1 or CES2, whereas PI was extensively hydrolyzed (90.2 ± 0.7%, 14.3 ± 1.1%, mean ± S.E.M.). In mice, PI was nearly completely hydrolyzed. Intravenous administration of PI-PEG resulted in significant levels in blood and in colon cancer xenografts (xenograft values in parentheses): area under the curve for 0–24 hours = 2351 (2621) (nmol/g) × h; Cmax = 1965 (886) nmol/g; Tmax = 0.08 (2) hour. The blood levels of ibuprofen, its main hydrolytic product, were minimal. Compared with controls, PI-PEG inhibited the growth of the xenografts by 74.8% (P < 0.01) and reduced intestinal tumor multiplicity in Apcmin/+ mice by 73.1% (P < 0.01), prolonging their survival (100% versus 55.1% of controls; P = 0.013). Pegylation protects PI from esterase hydrolysis and improves its pharmacokinetics. In preclinical models of colon cancer, PI-PEG is a safe and efficacious agent that merits further evaluation.

Management of abdominal and pelvic abscess in Crohn’s disease

Patients with Crohns disease may develop an abdominal or pelvic abscess during the course of their illness. This process results from transmural inflammation and penetration of the bowel wall, which in turn leads to a contained perforation and subsequent abscess formation. Management of patients with Crohns related intra-abdominal and pelvic abscesses is challenging and requires the expertise of multiple specialties working in concert. Treatment usually consists of percutaneous abscess drainage (PAD) under guidance of computed tomography in addition to antibiotics. PAD allows for drainage of infection and avoidance of a two-stage surgical procedure in most cases. It is unclear if PAD can be considered a definitive treatment without the need for future surgery. The use of immune suppressive agents such as anti-tumor necrosis factor-α in this setting may be hazardous and their appropriate use is controversial. This article discusses the management of spontaneous abdominal and pelvic abscesses in Crohns disease.

Virtual colonoscopy vs optical colonoscopy

IMPORTANCE OF THE FIELD: The high prevalence of colon carcinoma combined with the low compliance of currently recommended screening guidelines explains the continued high mortality rate of colon cancer. Utilizing a strategy of virtual colonoscopy (VC) in asymptomatic patients over 50, with optical colonoscopy (OC) follow-up for removal of detected adenomatous polyps may result in lowering the colon cancer death rate. However, the screening potential of VC has not yet been widely recognized. Debates and doubts of its potential benefits have been frequently seen in the literature since VC was first reported in 1994. AREAS COVERED IN THIS REVIEW: This article reviews the currently available screening options and discuss their advantages and drawbacks. TAKE HOME MESSAGE: VC has many advantages over the existing screening options and its several drawbacks can be mitigated so that it would become a valuable screening modality. A strategy that utilizes VC for population-based screening over the age of 50 and OC for screening high-risk individuals and those with positive VC findings would result in a significantly reduced rate of colon cancer deaths.

Human placenta-derived cells (PDA-001) for the treatment of moderate-to-severe Crohn's disease: A phase 1b/2a study

Background:PDA-001 (cenplacel-L), a preparation of placenta-derived mesenchymal-like adherent cells with immunomodulatory effects, previously demonstrated safety and tolerability in an open-label Crohns disease (CD) study. The current phase 1b/2a study evaluated the safety and efficacy of PDA-001 in subjects with moderate-to-severe CD. Methods:Subjects had active inflammation on colonoscopy or elevated fecal calprotectin and inadequate response to conventional therapy. Concomitant therapy with stable doses of immunomodulators and/or biologics was permitted. Subjects received 8 units of PDA-001 (1.5 × 108 cells per unit) in the phase 1b open-label study. In the phase 2a double-blind study, subjects were randomly assigned placebo, 1 unit, or 4 units of PDA-001 (2 infusions 1 wk apart). The primary endpoint was induction of clinical response (≥100 points and/or 25% decrease in Crohns Disease Activity Index) at 4 and 6 weeks. Results:Fifty subjects were enrolled (safety analysis, 50 subjects; efficacy analysis, 48 subjects). Four subjects received 8 units of PDA-001 (phase 1b study); 46 subjects were subsequently randomized to 1 or 4 units of PDA-001 or placebo (phase 2a study). The primary endpoint was achieved in 10/28 (36%) of PDA-001 subjects compared with placebo (0%, P = 0.026). Clinical remission was achieved in 4/28 (14%) of PDA-001 subjects compared with placebo (0%, P = 0.3). One treatment-related serious adverse event occurred (systemic hypersensitivity reaction at 8 units). In the phase 2a study, serious adverse events occurred in 9/28 (32%) of PDA-001 subjects and 1/16 (7%) of placebo subjects. Conclusions:A 2-infusion regimen of PDA-001 induced clinical response in subjects with moderate-to-severe CD. Additional studies are warranted.