bluuebunny/crossref_metadata_2025_split huggingface dataset:
A233 VEDOLIZUMAB FOR STEROID & INFLIXIMAB-REFRACTORY ICI-COLITIS
Authors: Klemm N K , Trasolini R , Chahal D , Donnellan F 
Published: February 2020

Abstract

Background
Immune checkpoint inhibitors (ICI), such as anti-PD1, improve survival in melanoma, renal carcinoma and prostate cancer. However, by disinhibiting the immune system, these treatments cause significant immune-related adverse events (irAE), including colitis. For ICI-colitis, guidelines suggest escalating from observation to steroids to infliximab, without strong evidence for additional options should these fail. Vedolizumab has been used in a small number of cases for steroid-refractory or dependent ICI-colitis; only 9 cases have been reported in patients who failed infliximab therapy with a response rate of 67%.

Aims
To discuss a case of ICI-colitis that failed multiple steroid courses and infliximab infusions, but achieved remission with vedolizumab.

Methods
A 65-year-old male with malignant melanoma was randomized to adjuvant nivolumab +/- ipilimumab and developed non-bloody diarrhea. Despite loperamide, diarrhea worsened to 4–5 bowel movements daily. Stool cultures and C. diff were negative and 85mg of daily prednisone was started, while the ICI was held for 8 weeks. After a 2nd steroid taper, diarrhea recurred and the patient received 2 infliximab infusions 18 days apart. Despite initial improvement, biopsies demonstrated colitis and he underwent a 3rd infusion with little response. Clinical and biopsy-confirmed remission was only achieved once 2 vedolizumab infusions were given.

Results
Colitis is the most common ICI irAE, ranging in severity from mild to perforation and death. The incidence of grade 3 and 4 colitis, which require ICI discontinuation, is 1.3% for anti-PD1 and 13.6% in combination therapy. The severity of irAE is positively correlated with malignancy response and stopping ICI risks recurrence. Those that fail irAE medical management may require surgery. Thus, there is an impetus to continue the ICI and provide effective medical management for irAE.
ICI-colitis guidelines are based on the CTCAE diarrhea classification and suggest supportive management and ICI continuation for grade 1. For grade 2, the ICI is held and steroids are started; infliximab is added for grades 3 and 4. However, 33–66% of patients are steroid-refractory or dependent; and patients may be infliximab non-responders, or unable to tolerate systemic side effects.
Vedolizumab, an anti-α4β7-integrin, acts locally to inhibit T cells in the bowel wall, reducing inflammation in IBD. Recent reports, including ours, suggest usefulness in steroid and infliximab-refractory ICI colitis after only 2–4 infusions. When the inflammatory burden is high, the response rate is &gt;80% and given its gut-specificity, side effects are minimal compared to infliximab. Although further evaluation is required, using vedolizumab as second-line therapy is reasonable.

Conclusions
Given vedolizumab’s safety and gut-specificity, it should readily be considered in the treatment of ICI irAE.

Funding Agencies
None
A235 THE INFLUENCE OF IL10 ON COLITIS DEVELOPMENT IN NOD2 DEFICIENT MICE
Authors: Gryfe M D , Croitoru K , Goethel A , Luchak A 
Published: February 2020

Abstract

Background
Inflammatory bowel disease (IBD) risk genes include interleukin-10 (IL10) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Although their specific roles in intestinal inflammation are unclear, these proteins are involved in modulating host-microbe interactions and intestinal homeostasis.

Aims
Since IL10 is an anti-inflammatory cytokine that maintains intestinal homeostasis, we hypothesized that mice deficient for both IL10 and NOD2 would be more susceptible to colitis than mice with only the NOD2 deletion.

Methods
In-house generated NOD2-/- x IL10-/- (double knockout) and NOD2-/- x IL10+/+ littermate mice of varying ages (3–20 weeks of age) were weighed and stools samples were collected at weekly intervals. Lipocalin-2 (LCN-2) levels were quantified in stool by ELISA. A subset of mice from each genotype received 3.5% dextran sulfate sodium (DSS) supplemented water for 5 days starting at eight weeks of age. Mice were sacrificed after two days of regular water, on day 8.

Results
Untreated NOD2-/- x IL10+/+ mice showed higher fecal LCN-2 compared to NOD2-/- x IL10-/- mice at all ages, although this trend was not significant. Within DSS-treated mice, LCN-2 levels in stool collected at sacrifice (on day 8) were significantly higher in NOD2-/- x IL10+/+ mice, compared to NOD2-/- x IL10-/- mice. Moreover, only 50% (2 of 4) of the NOD2-/- x IL10+/+ DSS-treated mice survived to day 8, whereas all four NOD2-/- x IL10-/- DSS-treated mice survived.

Conclusions
Fecal LCN-2 indicates the extent of neutrophil infiltration, which is reflective of the severity of intestinal inflammation. As such, LCN-2 levels suggest that NOD2-/- x IL10+/+ mice have higher baseline inflammation and are more susceptible to DSS-induced colitis than double knockout NOD2-/- x IL10-/- mice. These results are contrary to our hypothesis that combining IL10 and NOD2 deficiency would increase colitis susceptibility as compared to NOD2 deficiency alone. This suggests that the absence of IL10 may actually reduce the severity of DSS-induced colitis in NOD2 deficient mice. The role of IL10 in modulating the gut microbiome using this model remains to be assessed.

Funding Agencies
CAG
A236 REAL LIFE HEALTH CARE UTILIZATION IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN THE ERA OF BIOLOGICS
Authors: Tchogna S A , Yang X , Deslandres C , Jantchou P 
Published: February 2020

Abstract

Background
The burden associated with the management of pediatric patients with inflammatory bowel disease (IBD) has been rising over the past years as the incidence of IBD is increasing in children. In addition, the widespread use of biologics and a treat-to-target approach also contributes to the increase of healthcare utilization.

Aims
The purpose of this study was to assess the health care services utilization and the associated factors in a prospective cohort of children diagnosed with IBD in Quebec.

Methods
Patients diagnosed from 2013 to 2015 and followed up until the transfer to adult care were identified in our IBD database. Data on IBD related services and treatments: imaging procedures, hospitalizations and outpatient visits, medications from diagnosis to transition was extracted. We analyzed the healthcare utilization according to the baseline disease severity (pediatric Crohn’s disease activity index (PCDAI) or pediatric ulcerative colitis activity index (PUCAI)) at diagnosis, and according to exposition to intravenous biologics.

Results
A total of 144 patients were included in the study [(77 males), Crohn’s disease (98), Ulcerative Colitis (31) and IBD-unclassified (15); median (interquartile(IQR)) age at diagnosis 15.2(14.3–16.3)]. The median(IQR) duration of follow up at the IBD clinic was 2.9 (1.8–3.9) years. The median (min-max) number of imaging procedures varied largely: esophagogastroduodenoscopy 1(0–2), Colonoscopy 1(1–6), abdominal ultrasound 1(0–13), abdominal MRI 1(0–4), tomodensitometry 0(0–2), Bone densitometry 1(0–5). Patients had various follow-up encounters (median (min-max)): outpatient visits 9 (1–28), IBD nurses phone follow-up 4(0–33). A total of 64.6% of patients had at least one hospitalization [median(min-max) number 1(0–10); median duration 4(0–150 days)] and 35.41% had at least one emergency room visit. Baseline disease severity did not predict the disease burden: the mean number of encounters was 3.0 /year in the moderate/severe group as compared to 2.5/year in the mild group; P= 0.61. Among the, 63.5% of patients exposed to an intravenous biologic (Infliximab or Vedolizumab), those exposed earlier (&lt;3 months after diagnosis) used more health care services (mean = 3.3/year) than those exposed later (mean =2.23/year); P &lt;0.0001. In addition, the median (interquartile (IQR)) cumulative days of healthcare utilization (missing school days) for patients treated with intravenous biologics was 48.5 (32.4–67.9) days during pediatric care.

Conclusions
Adolescents with IBD have several encounters between the diagnosis and transition to adult care. Disease severity at diagnosis was not related to a higher level of health services utilization during follow-up. However, treatment with intravenous biologics was associated with a high health service utilization and school missing during follow-up.

Funding Agencies
None
A239 INFLAMMATORY BOWEL DISEASE PSYCHOTHERAPY PROTOCOL: GUT-DIRECTED COGNITIVE BEHAVIOURAL THERAPY, CLINICAL HYPNOSIS, AND EMOTION REGULATION COPING SKILLS DEVELOPMENT
Authors: Paulton J P , Prevost J 
Published: February 2020

Abstract

Background
IBD patients have a heightened risk for mental health illness, but general psychotherapy has shown mixed results. This psychotherapy protocol specialized for IBD patients uses recommended mental health therapies to treat specific chronic mental health illness. Therapy focuses on practicing CBT, clinical hypnosis, and emotion regulation healthy coping skills to self-manage chronic mental health symptoms. Standard therapies for acute mental illness, e.g. anxiety, depression, and suicidality, should be used as appropriate.

Aims
Aims of psychotherapy in IBD include improvement of mental health, symptoms management, quality of life (QOL), and adherence to medical treatments. Cognitive behavioural therapy (CBT) changes maladaptive coping behaviours and thinking. Clinical hypnosis improves somatic symptoms, e.g. chronic pain, nausea, and cramping. Emotion regulation improves ability to process stressful emotions, and has been shown to be affected by chronic diseases, including moderate to severe Crohn’s disease.

Methods
Patients learn to self-manage chronic mental health symptoms with healthy coping skills. CBT allows patients to identify maladaptive coping behaviours and thinking. Healthy coping behaviours and thinking patterns are chosen, supported, and adapted to. Clinical hypnosis uses relaxation techniques, e.g. progressive muscle relaxation, visualizations, and positive suggestions as a complimentary therapy for somatic symptoms. Emotion regulation develops tolerance and healthy processing of stressors.

Results
Therapy effectiveness is evaluated by improvements in patients’ mental health, symptoms management, QOL, and adherence to medical treatments. Mental health improvement, QOL, and emotion regulation are monitored by patient self-report, e.g. questionnaires. Maladaptive coping behaviours and thinking changed using CBT are individual to each patient. Somatic symptoms improved using clinical hypnosis are determined by monitoring or patient self-report. Adherence to medical treatments, as appropriate, is monitored.

Conclusions
This IBD psychotherapy protocol uses gut-directed CBT, clinical hypnosis, and emotion regulation therapies, designed to improve mental health, symptoms management, QOL, and adherence to medical treatments. Healthy coping skills treat maladaptive coping behaviours and thinking, somatic symptoms, and emotion dysregulation. Chronic mental health illness associated with IBD, is treated using this specialized psychotherapy.

Funding Agencies
None
A246 POPULATION WIDE STUDY OF THE EPIDEMIOLOGY AND OUTCOMES OF ANTI-TNF DOSE AUGMENTATION IN INFLAMMATORY BOWEL DISEASE
Authors: Elias E , Singh H , Bernstein C N , Targownik L 
Published: February 2020

Abstract

Background
Inflammatory bowel disease (IBD) patients who experience loss of response to anti-tumor necrosis factor (anti-TNF) therapy are often treated with augmented doses of anti-TNF to recapture response. Despite this, factors associated with dose augmentation and treatment outcomes following dose augmentation remain largely undefined.

Aims
To examine the epidemiology of anti-TNF dose augmentation and determine the associated treatment outcomes among a province-wide cohort of anti-TNF treated IBD subjects.

Methods
The University of Manitoba Inflammatory Bowel Disease Epidemiological Database was used to identify patients receiving infliximab or adalimumab maintenance therapy for IBD in the Canadian province of Manitoba. Anti-TNF dose augmentation was defined as a ≥50% increase in anti-TNF dose or a shortening of dosing interval to ≤42 days for infliximab or ≤10 days for adalimumab. Anti-TNF failure was defined as corticosteroid use, IBD-related hospitalization, resective IBD surgery, or change in anti-TNF agent. Competing risks regression using a proportional subhazards model was used to determine the associations between dose augmentation, anti-TNF failure, anti-TNF discontinuation and a number of patient, disease, and treatment factors.

Results
871 persons (624 Crohn’s disease (CD), 247 ulcerative colitis (UC)) using anti-TNF maintenance therapy were identified. Cumulative incidence of dose augmentation among continued users was 25.7% at 90 days, 52.3% at 1 year, and 72.8% at 5 years. Anti-TNF failure occurred in 261 of 575 dose augmented subjects, with corticosteroid use the most common failure-defining event. Failure of standard dose anti-TNF in the 90 days preceding dose augmentation was strongly associated with failure of dose augmentation (HR 2.98 (2.27–3.93); p&lt;0.0001). Persons with CD were less likely to receive corticosteroids but more likely to switch anti-TNF agents than persons with UC.

Conclusions
Rates of adverse IBD outcomes remain high after dose augmentation, particularly when dose augmentation is undertaken shortly after (or in response to) one of these adverse events. Our data suggest that dose augmentation may not be as effective as uncontrolled observational studies have indicated.

Funding Agencies
None
A263 MICE CHALLENGED WITH DNBS FOUR DAYS AFTER INFECTION WITH THE RAT TAPEWORM HYMENOLEPIS DIMINUTA ARE PROTECTED FROM COLITIS
Authors: Li S , Wang A , McKay D M 
Published: February 2020

Abstract

Background
Helminth therapy for colitis is supported by data from murine models, including infection with H. diminuta inhibiting dinitrobenzene sulphonic-acid (DNBS)-induced colitis. Considering H. diminuta as a candidate helminth therapy the kinetics of infection in the context of inflammation should be addressed. Reciprocally, it is important to know if colitis alters the immune response to the helminth.

Aims
1) Assess DNBS-colitis in mice infected 4-days previously with H. diminuta. 2) Determine in DNBS-induced colitis affects the outcome of infection with H. diminuta.

Methods
Male BALB/c mice were infected by gavage with five H. diminuta and four days later were challenged with DNBS (3 mg, ir.). Disease was assessed 3 days later (i.e. day 7-post H. diminuta) by colon length, disease activity score and histopathology (n=9–14 mice, 3 experiments). Alternatively, on day three post-DNBS, mice were infected with H. diminuta and worm infectivity and splenocyte Th2-cytokine production assessed at 8 days post-infection (n=5–9 mice, 1 experiment).

Results
Mice challenged with DNBS at 4-days post-infection were significantly protected from colitis, with 2/14 mice requiring humane euthanization for disease severity compared to 6/13 in the DNBS-only group. Splenocyte production of IL-4, IL-5 and IL-10 was increased in the H. diminuta-only group compared to control mice: DNBS-only treated mice showed reduced levels of all three cytokines and H. diminuta+DNBS mice had cytokine levels not different from H. diminuta-only infected mice. DNBS-colitis prior to infection did not affect the increase in systemic TH2 immunity evoked by H. diminuta, but did result in greater intestinal worm burdens.

Conclusions
The data suggest (1) the window of opportunity for H. diminuta to suppress colitis in a prophylactic regimen is at least 4–8 days post-infection, and (2) H. diminuta administered to mice at the peak of colitis severity mobilizes TH2 immunity that could promote quicker recovery from colitis.

Funding Agencies
CAG, CCC, NRCNSERC
A264 HELMINTH-INFECTION MOBILIZES HOST AND MICROBIAL FACTORS THAT CO-OPERATE TO SUPPRESS CHEMICAL-INDUCED COLITIS IN MICE
Authors: Shute A J , Callejas Pina B E , Jayme T S , Wang A , Buret A , McKay D M 
Published: February 2020

Abstract

Background
Infection with helminth parasites suppresses inflammation in murine model systems; for example, IL-10 is important in Hymenolepis diminuta-inhibition of DNBS-induced colitis. Bacteria-derived products can have anti-inflammatory effects. Given that infection with H. diminuta, or other parasitic worms, results in perturbation of the gut microbiota, the present study tested a role for bacteria in helminth-suppression of colitis by assessing reciprocity between IL-10 and butyrate signaling in the amelioration of colitis.

Aims
To determine if a functional relationship exists between IL-10 and butyrate in the inhibition of colitis observed following infection with the lumen-dwelling tapeworm, Hymenolepis diminuta.

Methods
Colitis was induced in male BALB/c mice by intra-rectal dinitrobenzene sulphonic acid (DNBS) (3 mg/~22g mouse), with necropsy and assessment 3 days later. Mice received either infection with five H. diminuta cysticercoids by gavage or daily butyrate enemas or acetate in their drinking water. Immunostaining assessed IL-10R protein expression on formalin-fixed sections of colon. The murine IEC4.1 epithelial cell line and epithelial organoids were treated with butyrate and mRNA for the IL10Rα chain assessed, as was colonic tissue from mice.

Results
Mice infected with H. diminuta or receiving butyrate enemas (n=8–12) were protected from DNBS-induced colitis as gauged by colon length, and macroscopic disease and histopathology scores. Addition of acetate to the drinking water resulted in a more modest anti-colitic effect. Suppression of colitis was accompanied by increased epithelial expression of IL-10 in butyrate- and H. diminuta-treated mice, with the later also showing upregulation of the IL-10R on lamina propria cells; an effect negated by co-treating the mice with broad spectrum antibiotics. In vitro analyses revealed increased IL10Rα mRNA in butyrate-treated epithelia (n=4).

Conclusions
This study begins to tease apart the host (i.e. IL-10) and bacterial (i.e. butyrate) molecules that mediate H. diminuta-evoked suppression of colitis in a murine model. These proof-of-principle data suggest that knowledge of the individual patient (i.e. immunological basis of their disease and their microbiota) may be a critical determinant of the success or failure of helminth therapy.

Funding Agencies
CAG, CCCNSERC
A265 SERIAL FECAL MICROBIOTA TRANSPLANT PLUS FIDAXOMICIN IN THE TREATMENT OF SEVERE OR FULMINANT CLOSTRIDIOIDES DIFFICILE INFECTION
Authors: Russell L , Roach B , Yang D Y , Wang C , Wine E , Saxinger L , Wong K , Kao D H 
Published: February 2020

Abstract

Background
Severe and fulminant Clostridioides Difficile infection(CDI) is associated with increased mortality and morbidity. Current guidelines recommend high dose vancomycin with metronidazole for treatment. Surgery is a high risk for patients failing medical therapy partly due to multiple comorbidities. Emerging evidence suggests efficacy of sequential fecal microbiota transplantation(FMT) by colonoscopy combined with vancomycin in patients failing maximal medical therapy. Fidaxomicin is non-inferior to vancomycin in treating CDI; however, it has not been studied in severe/fulminant cases. It is not known if FMT by enema combined with fidaxomicin is efficacious and safe in this patient population.

Aims
This single center, prospective, open-label pilot study aimed to determine the efficacy and safety of combined sequential FMT by enema plus fidaxomicin in severe or fulminant CDI not responding to maximal medical therapy. Primary outcome was resolution of diarrhea 2 weeks following final FMT. Secondary outcomes were resolution of diarrhea 8 weeks following final FMT, safety of proposed treatment protocol and colectomy rate.

Methods
Consecutive patients with severe or fulminant CDI, who fulfilled study inclusion criteria were recruited. Sequential cycles of FMT, administered by enema daily over three days(720cc followed by 360cc and 180cc), plus fidaxomicin 200mg PO BID were given. Clinical symptoms and inflammatory markers were monitored during the study and subsequent cycles of FMT were administered when clinical or biochemical improvement plateaued. A final FMT was administered with CDI resolution.

Results
A total of three patients were enrolled between Jan 22 to Aug 8, 2019, shown in Table 1. One patient had fulminant CDI due to shock, and the others had severe CDI. All had severe pseudomembranous colitis seen on endoscopy at enrollment. Two of three patients reached both primary and secondary outcomes with 2 FMT cycles. The only patient who did not reach the primary was successfully managed with long term vancomycin suppression. This patient had failed multiple FMTs prior to enrollment. There were no adverse events noted and no colectomy was required during this study.

Conclusions
This pilot study is the first to demonstrate efficacy and safety of combined sequential FMT by enema and fidaxomicin in treating severe or fulminant CDI patients. An adequately powered study is required to validate these findings.

Funding Agencies
CIHRAlberta Health Services, University of Alberta Hospital Foundation
A275 REVISITING THE DIAGNOSTIC YIELD OF ERCP BRUSH CYTOLOGY FOR INDETERMINATE BILIARY STRICTURES
Authors: Nur A , Boerner S , Edwards L , Ryan K , James P 
Published: February 2020

Abstract

Background
Endoscopic Retrograde Cholangiopancreatography (ERCP) brush cytology is the most frequently used tool for sampling indeterminate biliary strictures. Previous studies have demonstrated that the diagnostic yield of brush cytology for malignant biliary strictures is 60%. With improved diagnostic tools, sampling techniques and specimen processing, the yield of ERCP brush cytology may be higher.

Aims
To assess the diagnostic yield of ERCP brush cytology in patients with indeterminate biliary strictures and to determine factors associated with positive diagnosis.

Methods
This is a retrospective study of all patients who underwent ERCP with brush cytology at University Health Network (UHN) from October 2016 to September 2019. The cytological samples were taken as follows: the cytology brush is introduced into the stricture ten times under direct fluoroscopy guidance. The brush was cut and placed into a methanol based buffered solution (CytoLyt®). Residual sample was then flushed out of the catheter with the solution and into the sample container. Patient demographic, clinical, procedural and pathological data was collected by chart review. All patients were followed for a minimum of three months after their index ERCP. Post-ERCP sampling via repeat ERCP brushings, endoscopic ultrasound fine needle biopsy, percutaneous biopsy or surgical resection was recorded.

Results
A total of 97 patients underwent ERCP with brush cytology during the study period (43 females, median age 69 years). Fifty-nine patients (84%) were diagnosed with malignancy via ERCP brush cytology. Using follow up sampling, surgical resection and clinical follow up as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 84%, 100%, 100%, and 71% respectively. Patient demographics, degree of cholestasis or stricture location had no significant impact on these outcomes.

Conclusions
This study shows a high diagnostic yield for ERCP with brush cytology for patients with indeterminate biliary strictures. Large prospective studies using updated tools, techniques and specimen handling processes are needed to confirm our observations.

Funding Agencies
None