Quality of Care and Outcomes Among Hospitalized Inflammatory Bowel Disease Patients: A Multicenter Retrospective Study.

BACKGROUND: Half of patients with inflammatory bowel disease (IBD) require hospitalization. We sought to characterize inpatient quality indicators of care and outcomes during IBD-related hospitalizations at 4 major IBD referral centers in Canada. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD admitted from 2011 to 2013 to tertiary centers in Toronto, Montreal, Ottawa, and Vancouver. We assessed the following inpatient indicators of care: pharmacological venous thromboembolism (VTE) prophylaxis, Clostridium difficile testing, and medical rescue therapy for steroid-refractory ulcerative colitis (UC). We also evaluated rates of VTE, C. difficile infection, and IBD-related surgery. RESULTS: There were 837 patients hospitalized for IBD (Crohn's disease, 59%; UC, 41%). The proportion of patients with IBD who received VTE prophylaxis and C. difficile testing were 77% and 82%, respectively, although these indicators varied significantly by center and admitting specialty. Patients admitted under surgeons were more likely than those admitted under gastroenterologists to receive VTE prophylaxis (84% versus 74%, P = 0.016) but less likely to be tested for C. difficile (41% versus 88%, P < 0.0001). The rate of VTE was the same for those who did and did not receive VTE prophylaxis (2.2 per 1000 hospital-days). Among the 14 VTE events, 79% had received prophylaxis, but only 36% within 24 hours of admission. Among steroid-refractory UC patients, 70% received rescue therapy within 7 days of steroid initiation. The proportion of patients with UC and CD who required respective bowel surgery was 18% and 20%, respectively. CONCLUSIONS: There are opportunities to optimize quality of care among hospitalized patients with IBD.

A case series of two glomus tumors of the gastrointestinal tract.

Two recent cases of glomus tumors (GTs) of the gastrointestinal tract presented with symptoms of GI bleeding. GTs, typically benign lesions of mesenchymal origin, are rarely seen in the GI tract, and most commonly involve the distal appendages. This case series discusses the tumor biology, presentation, imaging, endoscopic findings, pathology and management of GTs. While diagnosis of GTs is typically made on final surgical pathology, there are defining characteristics that can separate a GT from a gastrointestinal stromal tumor on endoscopic ultrasound (EUS) and CT imaging. The classic pathological findings are discussed, and surgical decision-making is reviewed. New developments in the form of EUS-guided biopsy and endoscopic submucosal dissection present new avenues for diagnosis and treatment of submucosal lesions of the GI tract, including GTs. While typically a benign tumor requiring no adjuvant therapy, this study discusses some very rare cases of metastatic GT in the literature.

Vedolizumab for ulcerative colitis and Crohn's disease: results and implications of GEMINI studies.

Vedolizumab (VDZ) is a selective antibody against α4ß7-integrin, which targets leukocyte trafficking in the gastrointestinal tract. The GEMINI studies are Phase 3, randomized, placebo-controlled trials to assess the efficacy of VDZ in induction and maintenance of moderately to severely active ulcerative colitis (GEMINI 1) and Crohn's disease (GEMINI 2). Included in these studies are patients who have failed TNF-α antagonist therapy. GEMINI 1 showed that VDZ is an effective agent in induction and maintenance of ulcerative colitis. GEMINI 2 met one of two primary end points in the induction phase showing that VDZ is more likely to induce clinical remission compared with placebo. VDZ is an effective agent in the maintenance of Crohn's disease. These studies pave the way to a new class of medications for treatment of inflammatory bowel disease.

Time of infliximab therapy initiation and dose escalation in Crohn's disease.

AIM: To determine if early initiation of anti-tumor necrosis factor therapy affects the need for dose escalation. METHODS: This was a retrospective review of patients receiving infliximab therapy for Crohn's disease (CD) at two outpatient gastroenterology clinics during July 2009 to October 2010. All patients included in the study were biologic agent naïve and had moderate to severe CD (Harvey Bradshaw index > 8). Patients were divided into groups based on length of time between diagnosis to therapy initiation and concurrent immunosuppressant therapy. Kaplan-Meier survival analysis was used to compare the time to dose escalation for the four groups. RESULTS: There were 68 patients, 51% female and 49% male, with an average age at diagnosis of 24.7 ± 11.9 years. The average age at infliximab initiation was 34.8 ± 14.8 years. Of the 68 patients, 19% initiated inflixiamb within 2 years of diagnosis, and 51% had concurrent immunosuppressant therapy at the time of therapy initiation. Fifty percent of patients required dose escalation and the median time from therapy initiation to dose escalation was 10 mo (interquartile range: 5.3-14.8). There was a statistically significant higher probability of requiring dose esclataion in patients who initiated biologic therapy within 2 years of diagnosis, without concurrent immunosuppressant therapy (P < 0.01). CONCLUSION: Those who receive infliximab within 2 years of CD diagnosis require more intense immunosuppressant therapy than those who received infliximab later.

Follow-up of participants in the Canadian Association of Gastroenterology Scholars' Program, 2006 to 2012.

The Canadian Association of Gastroenterology (CAG) Scholars' Program (previously known as the Bright Lights Course) is designed to encourage trainees to consider a subspecialty career in gastroenterology. A formal analysis of the Scholars' Program performed in 2007 revealed that 82% of participants invited to the program pursued or were planning to pursue a career in gastroenterology. The positive results are consistent with the CAG's strategic plan of developing "the next generation of gastroenterology clinical practitioners, researchers, educators, and leaders" and to "attract, train, and retain the best and the brightest to gastroenterology". The present study was a follow-up analysis of participants in the Scholars' Program between 2006 and 2012. Although 93.1% of participants had an interest in gastroenterology before attending the Scholars' Program, the majority (68.7%) reported a greater interest in gastroenterology after the program. Similar to the study from 2007, the present study again illustrates the importance and success of the Scholars' Program in generating interest and retaining candidates in gastroenterology.

Argon plasma coagulation for the treatment of hemorrhagic radiation colitis.

Radiation colitis is a common consequence of pelvic radiation. Its complications may include anemia due to chronic bleeding requiring transfusions. Many of these patients are managed with rectal medications which are often inadequate for control. Argon plasma coagulation (APC) has been well described for its efficacy in treating radiation proctitis. Here we present two cases in whom APC therapy was used to treat severe radiation colitis. We reviewed two cases originally seen at the regional cancer center (Cross Cancer Institute) in Edmonton, Alberta, Canada. Both patients received pelvic radiation for recurrent endometrial cancers and were referred for active bleeding secondary to radiation colitis that had required numerous transfusions. Radiation-induced telangiectasias were found from 10-50 cm in the sigmoid colon. Both patients had significant improvement of symptoms after one session of APC treatment set at 40-60 W and gas flow of 2.0 l/min. There were no complications from the procedures. Neither patient required blood transfusions after the treatment with improvement in their hemoglobin levels and were doing well at 3- and 6-month follow-up. APC can be used effectively to provide immediate and sustained resolution of symptoms in patients with radiation colitis.

Familial hypobetalipoproteinemia-induced nonalcoholic steatohepatitis.

Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. It is an autosomal co-dominant disorder, and depending on zygosity, the clinical manifestations may vary from none to neurological, endocrine, hematological or liver dysfunction. Nonalcoholic fatty liver disease is common in persons with FHBL, however progression to nonalcoholic steatohepatitis is unusual. We describe here a patient with a novel APOB mutation, V703I, which appears to contribute to the severity of the FHBL phenotype. He had liver enzyme abnormalities, increased echogenicity of the liver consistent with steatosis, very low LDL cholesterol at 0.24 mmol/l (normal 1.8-3.5 mmol/l) and an extremely low apolipoprotein B level of 0.16 g/l (normal 0.6-1.2 g/l). APOB gene sequencing revealed him to be a compound heterozygote with two mutations (R463W and V703I). APOB R463W has previously been reported to cause FHBL. Genetic sequencing of his first-degree relatives identified the APOB V703I mutation in his normolipidemic brother and father and the APOB R463W mutation in his mother and sister, both of whom have very low LDL cholesterol levels. These results suggest that the APOB V703I mutation alone does not cause the FHBL phenotype. However, it is possible that it has a contributory role to a more aggressive phenotype in the presence of APOB R463W.

Gastric polyps in patients with portal hypertension.

OBJECTIVES: Gastric hyperplastic polyps are usually associated with chronic gastritis including Helicobacter pylori gastritis and postantrectomy stomachs. Here, we report on a series of 12 patients with portal hypertension secondary to liver cirrhosis, who were found to have a unique histological type of gastric polyp on endoscopy. METHODS: Retrospective chart review of 12 patients with portal hypertension, who presented with histologically diagnosed gastric hyperplastic polyps. These polyps were reviewed and compared with hyperplastic polyps from 21 patients who did not have portal hypertension. RESULTS: The endoscopic appearances of portal hypertension-associated polyps varied considerably, with sizes ranging up to 18 mm. They were sessile or pedunculated, singular or multiple, found in the antrum or body of the stomach, and endoscopically appeared to be typical hyperplastic polyps. Histopathological examination, however, showed mucosal hyperplasia and extensive vascular proliferation and granulation tissue formation. CONCLUSION: The unique histological appearance of gastric hyperplastic polyps in patients with portal hypertension polyps is described. The exact pathogenetic mechanism of polyp formation is unclear although it seems possible that the underlying cause is mucosal injury that is vascular in nature rather than being secondary to surface inflammation. Although there is an emerging evidence of the neoplastic potential of usual hyperplastic polyps, the natural history of portal hypertension-associated polyps is unknown. Identification and management of portal hypertension-associated gastric polyps present a particular dilemma, as these patients often have coagulopathies and vascular ectasias. Therefore, the natural history and endoscopic features of gastric polyps arising in portal hypertensive patients warrants further exploration.

Quality-of-life outcomes after surgical correction of pectus excavatum: a comparison of the Ravitch and Nuss procedures.

PURPOSE: The purpose of this study was to compare clinical and health-related quality-of-life (HRQL) outcomes within a group of patients treated for pectus excavatum (PE). METHODS: A retrospective 3-year review of patients undergoing Nuss or Ravitch correction of PE was performed. Health-related quality-of-life assessment was performed using the Child Health Questionnaire (CHQ-CF87) and the 17-item Pectus Excavatum Evaluation Questionnaire, and results were compared between groups and with age-matched CHQ-CF87 normative data. RESULTS: Forty-three patients (39 males; 91%) underwent surgery; 19 (44%) by Nuss procedure. Duration of postoperative opioid analgesia and length of hospital stay (LOS) were significantly longer in Nuss patients. The overall survey response rate was 53%. The groups differed significantly in the CHQ on one item (Change in Health). On the Pectus Excavatum Evaluation Questionnaire, Nuss patients reported being "less bothered" by the appearance of their chest. Compared to Australian age-matched norms, the aggregate PE sample showed better scores for family activity domain and worse scores in mental health, general health perceptions, change in health, bodily pain, and self-esteem. CONCLUSIONS: Patients undergoing surgery for PE by either Nuss or Ravitch procedure have similar clinical and HRQL outcomes, but as a group have poorer HRQL scores than age-matched population norms.

Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation.

CD45 is a transmembrane, two-domain protein-tyrosine phosphatase expressed exclusively in nucleated hematopoietic cells. The Src family kinase, Lck, is a major CD45 substrate in T cells and CD45 dephosphorylation of Lck is important for both T cell development and activation. However, how the substrate specificity of phosphatases such as CD45 is achieved is not well understood. Analysis of the interaction between the cytoplasmic domain of CD45 and its substrate, Lck, revealed that the active, membrane-proximal phosphatase domain of CD45 (CD45-D1) bound to the phosphorylated Lck kinase domain, the SH2 domain, and the unique N-terminal region of Lck. The second, inactive phosphatase domain (CD45-D2) bound only to the kinase domain of Lck. CD45-D2 was unable to bind phosphotyrosine, and its interaction with the kinase domain of Lck was independent of tyrosine phosphorylation. The binding of CD45-D2 was localized to subdomain X (SD10) of Lck. CD45-D2 bound similarly to Src family kinases but bound Csk to a lesser extent and did not bind significantly to the less related kinase, Erk1. CD45 dephosphorylated Lck and Src at similar rates but dephosphorylated Csk and Erk1 at lower rates. Replacement of Erk1 SD10 with that of Lck resulted in the binding of CD45-D2 and the conversion of Erk1 to a more efficient CD45 substrate. This demonstrates a role for CD45-D2 in binding substrate and identifies the SD10 region in Lck as a novel site involved in substrate recognition.

Adenovirus vector-induced inflammation: capsid-dependent induction of the C-C chemokine RANTES requires NF-kappa B.

Adenovirus vectors for gene therapy activate responses in the host that result in acute inflammation of transduced tissues. Our previous studies in vivo demonstrate that chemokines, including the C-C chemokine RANTES (regulated on activation, normal T cell expressed and secreted), contribute to the acute inflammation induced by adenovirus vectors. Various first-generation adenovirus vectors, including adCMV beta gal, were equally capable of inducing the expression of RANTES 3 hr after transduction in epithelial HeLa and REC cells. Deletional analysis of the human RANTES promoter revealed that induction by adCMV beta gal required the elements spanning base pairs -90 to -25 of the gene. Electrophoretic mobility shift assays demonstrated that nuclear extracts from adCMV beta gal-transduced HeLa cells bound to an NF-kappa B site at position -54. Overexpression of I-kappa B alpha suppressed adCMV beta gal induction of RANTES, confirming that this process was dependent on the nuclear translocation of NF-kappa B. The coxsackievirus-adenovirus receptor (CAR)-independent, serotype 3 adenovirus was equally capable of inducing the expression of RANTES in HeLa cells. This observation suggested that binding to CAR was not specifically required in adenovirus vector-induced RANTES expression. The use of RGD peptides to block adCMV beta gal interactions with alpha(v)-integrins reduced RANTES expression but also transduction efficiency. In CAR-deficient P815 cells, binding of adCMV beta gal to alpha(v)-integrins without efficient cell transduction did not result in increased RANTES expression. Expression of human CAR in P815 cells increased the binding and transduction efficiency of adCMV beta gal and resulted in RANTES expression in these cells. These results suggest that the induction of RANTES by adenovirus vectors is dependent on efficient interaction with its cell surface receptors and vector internalization. Understanding the biology of the host response to adenovirus vectors will impact the design of future generations of these agents aimed at reducing their immunogenicity and improving their safety.

Activation of p38 and ERK signaling during adenovirus vector cell entry lead to expression of the C-X-C chemokine IP-10.

The use of adenovirus vectors for human gene therapy is limited by potent inflammatory responses that result in significant morbidity. In kidney-derived epithelial cells (REC), activation of extracellular signal-regulated kinase 1/2 (ERK) and p38 kinase (p38) pathways occurred within 20 min of transduction with the serotype 5 adenovirus vector AdCMV beta gal. Inhibition of ERK and p38 with U0126 and SB203580, respectively, reduced the expression of IP-10 mRNA following transduction with AdCMV beta gal. To determine the role of the coxsackievirus-adenovirus receptor (CAR) or alpha(v) integrins in the activation of ERK and p38 and the expression of IP-10, REC cells were transduced with the fiber-modified and RGD-deleted adenovirus vectors AdL.F(RAEK-HA) and AdL.PB(HA), respectively. Compared with the wild-type capsid vector Ad5Luc, transduction with AdL.F(RAEK-HA) and AdL.PB(HA) resulted in reduced ERK-p38 activation and less IP-10 mRNA expression. The decreased IP-10 expression induced by the tropism-modified vectors was due to diminished transduction, since increasing multiplicity of infection resulted in increased IP-10 expression. Inhibition of adenovirus penetration with bafilomycin A1 or ammonium chloride attenuated the activation of ERK-p38 and IP-10 mRNA expression following infection, suggesting that endosomal escape was required to trigger these pathways. In vivo, direct inhibition of ERK and p38 signaling pathways inhibited adenovirus vector-induced IP-10 expression in mouse liver 1 h following transduction. These results demonstrate the importance of signaling via ERK and p38 in the early host response to adenovirus vectors and will permit the development of novel strategies to improve the safety and efficacy of these agents in human gene therapy.