bluuebunny/crossref_metadata_2025_split huggingface dataset:
A75 ON THE TRAIL OF ALTERNATIVE LIGANDS AND SIGNALING PATHWAYS FOR LGR5
Authors: Dagenais Bellefeuille S , Arguin G , Gendron F 
Published: February 2020

Abstract

Background
Leucine-rich G protein coupled receptor-5 (LGR5) is a GPCR originally identified as a marker for intestinal stem cells but is now associated to stemness in numerous other tissues. R-spondins (RSPO) are the only reported ligands of LGR5, which upon receptor binding, potentiates the canonical Wnt/b-catenin pathway. Surprisingly, despite the presence of classical GPCR features such as conserved DRY and NPXXY motifs RSPO binding to LGR5 does not induce classical GPCR behaviors such as coupling to heterotrimeric G-proteins or engagement of b-arrestins. For this reason, LGR5 is still considered to be an orphan receptor.

Aims
Aberrant expression of LGR5 is a common feature of many cancers, including gastrointestinal cancers, but it is still unclear why LGR5 is pro-tumorigenic in some cancers, while anti-tumorigenic in others. One potential explanation is that LGR5 does not only signals through the Wnt/b-catenin pathway, but also to alternative pathways. Thus, the goals of this study were 1), to elucidate LGR5 signaling networks and 2), to identify new LGR5 ligands and activity modulators. We suggested that the intestinal lumen content could be a source of bioactive molecules that could act as alternative LGR5 ligands

Methods
All experiments were performed on HEK293 cells expressing recombinant LGR5 (HEK293/LGR5) and compared to control cells expressing empty vector. Characterization of LGR5 signaling network was initiated with LC MS/MS spectrometric analyses using cells stimulated with Wnt3a and RSPO1. To identify new LGR5 modulators, commercially available bacteria-derived metabolites (BDM) were tested on HEK293/LGR5 cells stimulated with Wnt3a and RSPO1 and assessed using the TOP-Flash luciferase system. Finally, a mouse intestinal lumen extract (ILE) was investigated in whole-cell impedance assay to detect if it contained native BDM or potential host-derived LGR5 ligands.

Results
Mass spectrometric analyses revealed distinct protein expression and phosphorylation profiles in HEK293/LGR5 cells stimulated with Wnt3a and RSPO1. The TOP/Flash luciferase assays showed that the flavonoid derivative 3,4-dihydroxyphenylacetic acid (DOPAC) and lipopolysaccharide (LPS) acted as negative regulators of LGR5, while butyrate had no effect. Interestingly, stimulation of HEK293/LGR5 with ILE induced a Gαq-like response in the impedance assay, while control cells did not respond.

Conclusions
Stimulation of LGR5 with Wnt and RSPO triggered a complex signaling network. In agreement with our hypothesis, some BDM such as DOPAC and LPS were indeed activity modulators of LGR5. Moreover, a still unidentified compound present in the ILE triggered a selective GPCR-like response in HEK293/LGR5 cells. Future works aim at identifying this putative LGR5 ligand(s) and establish the LGR5 interactome using proximity labeling and mass spectrometry.

Funding Agencies
NSERC, Université de Sherbrooke, FRQS
A80 ADVANCED ENDOSCOPIC RESECTION OF LARGE POLYPS & EARLY NEOPLASIA: OUTCOMES OF ENDOSCOPIC MUCOSAL RESECTION IN BRITISH COLUMBIA
Authors: Zhao B , Chahal D , Lam E , Donnellan F 
Published: February 2020

Abstract

Background
Recent advances have resulted in a new technique termed endoscopic mucosal resection (EMR). This procedure has been successful at removing large or complex polyps and achieving remission rates comparable to surgery. EMR can also be used to remove early, non-metastatic cancer and they are less invasive than surgery. However, they have been associated with their own complications, most serious of which being perforation. This procedure has recently become available in British Columbia for resection of both complex polyps and early established cancers in the colon.

Aims
Here we present patient outcomes of EMR procedures for the resection of colorectal polyps in British Columbia.

Methods
Retrospective data were collected on all EMR procedures done in Vancouver General Hospital and St. Paul’s Hospital (Vancouver, B.C.) from October 2012 (when procedure became available) to July 2019. Inclusion criteria were all adults who had undergone EMR for resection of polyps in the colon. Exclusion criteria were patients younger than 18 or patients who had EMR that resected polyps in the upper GI tract. Patients were referred to one of two endoscopists when one or more polyps suitable for EMR were identified during colonoscopy by other gastroenterologists. Collected data included patient demographics, polyp characteristics, procedure outcome, and complications.

Results
There were 211 EMR procedures performed on 182 patients (48.9% male). Patient age ranged from 27 to 86 (mean = 67.1). A total of 244 colon polyps were removed with an average size of 2.91 cm and ranged from 0.8 cm to 15 cm. Resected polyps had the following distribution: ascending colon (63.5%), transverse colon (10.2%), descending colon (5.7%), sigmoid colon (15.2%), and rectum (5.3%). Of those that reported resection type, 84.2% were piecemeal and 15.8% were en bloc. 40.9% of polyps were tubulovillous adenoma, 33.2% were tubular, 16.2% were sessile serrated, 6.4% were villous, and 3.4% were adenocarcinoma. Patients from 11 of the 211 EMR cases (5.2%) experienced post-procedure bleed and 4 of these 11 patients (36.4%) had been on anti-platelet or anti-coagulants (discontinued before procedure). Overall, patients from 51 (24.2%) EMR cases were on anti-platelet or anti-coagulants. 33 cases (15.6%) had residual polyps at the resection site that required additional endoscopic resection during follow-up and 14 patients (6.6%) required surgery. None of the EMR procedures resulted in perforation.

Conclusions
EMR is an effective minimally-invasive procedures that can be used to remove large, complicated colonic polyps and achieve long-term remission rate. The procedure has an acceptable risk profile, with complication and re-intervention rate similar or less than other procedures used to remove large, complicated polyps.

Funding Agencies
None
A81 POST COLONOSCOPY COLORECTAL CANCERS IN MANITOBA: A POPULATION-BASED ANALYSIS
Authors: Singh H , Derksen S , Sirski M , McCulloch S , Lix L M 
Published: February 2020

Abstract

Background
Recent consensus guidelines from the World Endoscopy Organization (WEO) recommend all jurisdictions report unadjusted rates of post colonoscopy (PC) colorectal cancers (CRC). Until recently, prior reports have mostly focused on PC-CRC in the CRC screening age groups.

Aims
We evaluated the rate and predictors of PC-CRC in the adult population for the province of Manitoba from 1990 to 2016.

Methods
Individuals 18+ years at CRC diagnosis were identified from the Manitoba Cancer Registry. Colonoscopies in the 3 years preceding CRC diagnosis were identified via linkage to Manitoba Health (MH) physicians billing claims. CRCs were classified, based on WEO recommendations, as: (1) detected CRC (colonoscopy up to 6 months before CRC diagnosis) and (2) PC-CRC-3y (colonoscopy 6–36 months before CRC diagnosis). Generalized linear models with generalized estimating equations (to adjust for clustering within endoscopy physicians) were used to test for differences in rates over 3-time intervals (1990/91 – 1999/00; 2000/01 - 2009/10; 2010/11 – Dec 31 2016), provincial region of performance of colonoscopy and identify other associations from the MH data.

Results
Overall, 10.5% of the 16,639 CRCs diagnosed in the study period and with colonoscopy in the preceding 3 years were PC-CRC-3y. CRCs diagnosed between April 2000 and March 2010 were more likely to be PC-CRC-3y than those diagnosed between April 2010 and December 2016 (odds ratio [OR] 1.18; 95% confidence interval [CI]: 1.03–1.37). Female sex (OR for male: 0.86; 95% CI: 0.77–0.94), IBD diagnosis (OR 3.04; 95% CI: 2.56–4.52), prior CRC (OR 5.41; 95% CI: 4.61–6.34), prior colonoscopy (OR 2.10; 95% CI 1.88–2.36), diverticulosis (OR 2.39; 95% CI: 2.16–2.6), colonoscopy by GP (OR: 1.62; 95% CI 1.16–2.26 vs. surgeons) were associated with increased odds of PC-CRC-3y. There were no regional differences, and no effect of colonoscopy volume or age greater than 75 (or lower than 50).

Conclusions
In Manitoba, the PC-CRC-3y rate decreased slightly in recent years. The study results of large number of PC-CRC-3y along with only a slight decrease in rates over the years, support calls for root cause analysis to evaluate individual cases of PC-CRC. An initial focus could be the groups with increased risk of PC-CRC.

Funding Agencies
Manitoba Health
A87 A NEW ERA: CIRCUMFERENTIAL ENDOSCOPIC SUBMUCOSAL DISSECTION FOR EARLY ESOPHAGEAL NEOPLASM AND BARRET’S ERADICATION
Authors: Markandey B , Robert B 
Published: February 2020

Abstract

Background
Endoscopic submucosal dissection (ESD) has become increasingly important over the last few years as the treatment of choice for early gastrointestinal malignancies. Esophageal adenocarcinoma is among the most rapidly rising malignancies associated with a poor 5-year survival rate. ESD is emerging as a novel minimally invasive treatment for superficial esophageal neoplasms. However, with increasing circumference of dissection, the rate of stricture increases with over 90% stricture rate reported with complete circumferential ESD (cESD). Currently, for superficial Barrett’s neoplasms the dysplastic lesion is resected and subsequent eradication of remaining Barrett’s is with radiofrequency ablation over multiple sessions.

Aims
To report on a case of cESD for intramucosal carcinoma and Barrett’s eradication with one procedure with the application of prophylactic dual steroid treatment (DST) for prevention of stricture.

Methods
We present the case of a 62-year-old female with C1M5 Barrett’s esophagus with pathology confirming high grade dysplasia with a focus suspicious for intramucosal adenocarcinoma. Staging CT excluded metastatic disease. Repeat endoscopy with magnification revealed multiple areas with highly irregular vascular and surface patterns with premature loss of acetowhitening reaction consistent with multifocal at least high-grade dysplasia. Subsequently, the entire segment of Barrett’s was removed via cESD. Histopathologic analysis of the resected tissue confirmed multifocal high grade disease with margins negative for dysplasia or intestinal metaplasia. The patient was started on DST with oral prednisone and topical (swallowed) budesonide along with sucralfate as prophylactic measures to prevent luminal stricturing.

Results
During the re-epithelization period the patient required 2 prophylactic dilations. Five months post-ESD, full clinical, endoscopic and histopathologic healing had been observed. There was complete squamous re-epithelization with normal squamous mucosa without stricture. The patient remains on a yearly endoscopic surveillance protocol.

Conclusions
cESD represents a novel therapeutic strategy for the definitive histologic and endoscopic eradication of superficial esophageal neoplasms along with remaining Barrett’s. In this patient, there were no complications and significant stricturing was prevented with DST. Multiple prior studies have assessed single steroid therapy as a therapeutic option for strictures. In this report, DST represents a novel regime in preventing severe strictures post cESD. Longer term follow-up and further reports are needed to confirm these findings.

Funding Agencies
None
A100 ORAL VANCOMYCIN THERAPY FOR CLOSTRIDIOIDES DIFFICILE INFECTION AND RISK OF INFECTION WITH GRAM-NEGATIVE ORGANISMS
Authors: Someili A , Alosail A , Brooks A , Irfan N , Leto D , Hadzic A , Alajmi A , Mertz D , Bader M 
Published: February 2020

Abstract

Background
Vancomycin is the recommended first-line therapy for mild to severe Clostridioides difficile infection (CDI). However, oral vancomycin is associated with disruption of the indigenous microbiota, predisposing patients to overgrowth of endogenous pathogens such as vancomycin-resistant enterococci.

Aims
The primary objective of the study is to examine the effect of the treatment regimens of CDI on the risk of infection with gram-negative organisms in adult patients treated for CDI.

Methods
A retrospective cohort study of 319 adult patients treated for CDI at Hamilton Health Sciences in the year 2015. A multivariate logistic regression analysis was performed to determine if oral vancomycin-based therapy is associated with an increased risk of infection with gram-negative organisms after adjustment for other factors.

Results
Eighty-one patients were excluded because of recurrent episodes of CDI within the same year or missing information. 238 patients were included in the final analysis. 48 (20.2%) patients had positive culture for gram-negative organisms after onset of CDI. Urine was the most common source for gram-negative organisms (39/48, 81.3%) followed by blood (8/48,16.7%). The most common isolated gram-negative organisms were Escherichia coli (18/48, 37.5%) and Klebsiella pneumonia (9/48, 18.8%).
The most common CDI treatment regimens were metronidazole monotherapy (137/238, 57.6%), vancomycin monotherapy (13/238, 5.5%), and combination therapy (88/238, 37.0%). Among patients who were treated with metronidazole monotherapy, vancomycin monotherapy, and combination therapy, 30(30/137, 21.9%), 3 (3/13,23.1%), and 15 (15/88, 17.1%) had positive culture for gram-negative organisms, respectively (P= 0.6).
Ninety-seven (97/238,40.8%) patients had severe CDI, 40 (40/97, 41.2%) were treated with metronidazole monotherapy, 5(5/97, 5.2%) with vancomycin monotherapy, and 52 (52/97, 53.6%) with combination therapy. 26 (26/141,18.4%) and 22 (22/97, 22.7%) had positive culture for gram-negative organisms among patients with non-severe and severe CDI, receptively (P= 0.7). In the multivariate analysis, neither type of CDI treatment regimen (P=0.2, 95% CI 0.30–1.31) nor CDI severity (P=0.4, 95% CI 0.67–2.69) was associated an increased risk of infection with gram-negative organisms after CDI onset.

Conclusions
Contrary to the reported literature, we did not find that oral vancomycin-based CDI treatment was associated with increased risk of infection with gram-negative organisms.

Funding Agencies
None
A105 ENDOSCOPIC MUCOSAL RESECTION (EMR) OF LARGE SESSILE POLYPS: DATA FROM A MULTI-CENTER HEALTH ZONE
Authors: Meng Z , Lee A , Liu E Y , Dhillon A S , Wong C , Sultanian R , Zepeda-Gomez S , van Zanten S , Kohansal A R 
Published: February 2020

Abstract

Background
EMR is the standard of care for management of large non-invasive colonic polyps. Current guidelines recommend repeat colonoscopy within 6 months after EMR of large sessile polyps to assess the EMR site for residual adenoma. We reviewed the outcomes and compliance to these guidelines in patients at the University of Alberta Hospital (UAH) and surrounding 7 hospitals.

Aims
The primary outcome was the proportion of patients who received a follow up colonoscopy within 180 days.

Methods
Retrospective data was collected on consecutive patients who had a large polyp resection (size &gt;2cm as documented per endoscopy report) from January 1st, 2014 to January 1st, 2016. Information was collected on patients from UAH as well as seven surrounding hospitals within the Edmonton geographic zone. Data was extracted from electronic health records.

Results
Of 258 patients identified patients, 250 had complete data. Of these 250 patients, 151 (60.4 %) were male and median age was 67 (IQR 60 - 72). Eighty-two cases (32.8%) were performed at UAH, with 168 cases (67.2%) at other hospitals. Polyps were removed by gastroenterologists (n=215, 86.0%), surgeons (n=26, 10.4%), and others (n=9, 3.6%).
Fifty-two patients (20.8%) had no formal follow up on electronic health records, while 198 patients (79.2%) had a repeat colonoscopy. 57 patients (29.1 %) had a repeat colonoscopy within 180 days. The median follow-up time was 224 days (IQR 172–365).
Of the 82 cases performed at UAH, 74 (90.2%) had follow up. Out of the 168 cases at the other hospitals, 124 (73.8%) had follow up (p&lt;0.01). Sixteen (21.9%) and 41 (33.3%) cases were followed up within 180days at UAH and other hospitals, respectively (p=0.09).
Of the 74 cases with follow up at UAH, 12 (15.7%) had residual tissue confirmed by pathology. Of the 124 cases at other hospitals, 26 (21.0%) had follow up (p=0.41). Median polyp size was 2.5cm (IQR 2.0cm - 3.5cm)

Conclusions
Only 29.1% of patients with large sessile polyp removal in the Edmonton zone had a repeat colonoscopy within 180 days. Patients with large polypectomy performed at the academic hospital were more likely to be followed up compared to non-academic hospitals. Further validation studies with larger data sets are needed. These findings highlight the need for standardized pathways to appropriately manage and survey large polyps post-EMR.

Funding Agencies
None
A111 SEVERE FAT MALABSORPTION IN A PATIENT POST ILEAL POUCH ANAL ANASTAMOSIS: A RARE PRESENTATION OF MICROSCOPIC ENTERITIS
Authors: Ricci M , Ropeleski M 
Published: February 2020

Abstract

Background
Microscopic enteritis (ME) is a rare enteropathy characterized by malabsorptive diarrhea and lymphocytic infiltration +/- collagen deposition in the subepithelial layer of the small bowel. Its etiology is unclear.

Aims
To elucidate a rare cause of fat malabsorption and vitamin deficiency in a patient with ulcerative colitis and an ileoanal pouch.

Methods
A 74 yo male with a prior IPAA was referred to Internal Medicine in August 2018 for a 36 kg weight loss over 18 months and &gt;16 bowel movements (BM) per day (baseline 6, no history of pouchitis). Celiac serology and infectious workup were negative. Medical management and nutritional supplements did not result in weight gain or improvement of diarrhea. He was admitted in June 2019 with ongoing weight loss, AKI, and signs of fat-soluble vitamin deficiency. A 72-hour fecal fat analysis showed an average fecal weight of 2100 g/d (ref &lt;250 g/d), and excretion of 70% of daily fat intake (ref &lt;7%). His fecal elastase (FE) was 147 µg/g, consistent with moderate pancreatic insufficiency (PI) with mild atrophy on CT. EGD and pouch endoscopy were macroscopically normal, with histological findings of intraepithelial lymphocytosis and mild villous blunting in the duodenum and afferent limb. CT enterography excluded small bowel abnormalities. He was started on pancreatic enzyme replacement and discharged. He returned with worsening diarrhea and AKI. He was treated with supportive care and sent home. In the ensuing 3 weeks, he had up to 24 BM per day and 4 kg of weight loss. He returned in August 2019 with AKI, lack of PO intake and worsened nutritional status. Re-examination of duodenal biopsies from June 2019 revealed an added finding of focal subepithelial collagen thickening. Budesonide was started.

Results
On budesonide, his symptoms improved within days. BMs decreased to baseline, and his ability to sustain PO intake improved. At his 4-week follow-up visit, BMs were stable with a 6 kg weight gain and no ensuing laboratory abnormalities.

Conclusions
ME is a rare enteropathy that presents with malabsorption. Fat-soluble vitamin deficiencies can develop with widespread physiological disruption of the mucosal surface. This patient was a diagnostic challenge. His steatorrhea and reduced FE levels led clinicians down a diagnostic pathway of PI. FE is the most common test used in the diagnosis of PI. Levels &lt;200 µg/g are abnormal. Specificity is highest in chronic pancreatitis; however, this decreases in the presence of mucosal atrophy (i.e. IBD and diffuse small bowel disease). Thus, FE could not delineate the cause of steatorrhea in our patient. We can surmise that he likely has diffuse disease that was underestimated on duodenal biopsy. This is supported by his response to budesonide. This case highlights the heterogeneity of clinical presentations of ME. Awareness can reduce patient morbidity.

Funding Agencies
None
A113 COST SAVINGS OF SEROLOGIC VERSUS BIOPSY PROVEN DIAGNOSIS OF PEDIATRIC CELIAC DISEASE
Authors: Wiepjes M , Huynh H Q , Wu J , Chen M , Shirton L , Zarrabi M , Turner J 
Published: February 2020

Abstract

Background
Celiac disease (CD) affects approximately one percent of the population in Canada and the United States. At present, endoscopic diagnosis (ED) of CD remains the gold standard in North America, despite mounting evidence and validated European guidelines for serologic diagnosis (SD). Within publicly funded healthcare systems there is pressure to ensure optimal resource utilization and cost efficiency, including for endoscopic services. At Stollery Children’s Hospital, Edmonton, Canada, we have adopted serologic diagnosis as routine practice since 2016.

Aims
The aim of this study is to estimate cost savings, i.e. hard dollar savings and capacity improvements, to the health care system as well as impacts on families in regard to reduced work days lost and missing child school days for SD versus ED. Initial cost saving data is presented.

Methods
Micro-costing methods were used to determine health care resource use in patients undergoing ED or SD from 2017–2018. SD testing included anti-tissue glutaminase antibody (aTTG) ≥200IU/mL (on two occasions), human leukocyte antigen (HLA) DQA5/DQ2, blood sampling, transport and laboratory costs. ED diagnosis included gastroenterologist, anesthetist, OR equipment, staff, overhead and histopathology. Cost of each unit of resource was obtained from the schedule of medical benefits (Alberta) and reported average ambulatory cost for day hospital endoscopy for Stollery Children’s Hospital determined in 2016; reported in CAN$.

Results
Between March 2017-December 2018, 473 patients were referred for diagnosis of CD; 233 had ED and 127 SD. Estimated cost for ED was $1240 per patient; for SD was $85 per patient (6.8% of ED cost). Based on 127 patients not requiring endoscopy and a cost saving of $1155 per patient there was a total cost savings of $146,685 over 22 months.

Conclusions
A SD approach presents a significant cost savings to the public health care system. It also frees up valuable endoscopic resources, and limits exposure of children to the immediate and long-term risks associated with anesthesia and biopsy. SD also decreases time to diagnosis and the cost of the process to families (lost days of school/work, travel costs etc.). Our costing data can be used in combination with mounting evidence on the test performance of SD versus ED to determine cost-effectiveness of serological diagnosis for pediatric CD. Given the potential for cost saving and more efficient operating room utilization, SD for pediatric CD warrants further investigation in North America.

Funding Agencies
None