bluuebunny/crossref_metadata_2025_split huggingface dataset:
P364 New insights into the molecular mechanisms of thalidomide in paediatric inflammatory bowel disease patients
Authors: Lucafò M , Bramuzzo M , Pugnetti L , Gerdol M , Greco S , Paci M , Curci D , Nonnis M , Renzo S , Lionetti P , Tommasini A , Decorti G , Stocco G 
Published: January 2020

Abstract

Background
Thalidomide is an effective drug in children with inflammatory bowel disease (IBD) refractory to standard treatments, however, its use is often limited by its safety profile, in particular for the risk of teratogenicity and peripheral neuropathy. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action but no data have been published on IBD patients. To identify determinants of thalidomide action in paediatric IBD, high-throughput microRNA (miRNA) and messenger RNAs (mRNA) profiles during treatment were analysed.

Methods
IBD patients responsive to thalidomide were enrolled. miRNA and mRNA profiles from peripheral blood obtained before and after 12 weeks of treatment were determined using next-generation sequencing. Differentially expressed genes were identified by fold change from the general linear model. In order to detect the potentially altered pathways, the hypergeometric test based on gene ontology annotations was used. The identification of putative mRNA targets of thalidomide sensitive miRNAs was performed by Targetscan database.

Results
Ten IBD paediatric patients (mean age 13.1 years, 6 males) were enrolled. Sequencing analysis identified 10 miRNAs (3 downregulated) and 252 mRNAs (76 downregulated) deregulated after treatment. Five upregulated miRNAs could putatively recognise the 3′UTR of several Hox genes, a group of transcription factors that play important roles in the development of structures such as limbs, lungs and nervous system. The hypergeometric test highlighted the altered pathways involved in inflammatory response, regulation of immune system, prostaglandin receptor activity and G protein-coupled receptor signalling. Among the 10 miRNAs deregulated by thalidomide, six could putatively regulate the differentially expressed mRNAs resulting from the analyses.

Conclusion
Thalidomide induces specific gene expression alterations, which could help to elucidate its molecular mechanism in paediatric IBD patients. miRNA results may suggest new molecular targets involved in the teratogenic effects of this drug. Moreover, mRNA profiles indicate a strong involvement of adenylate cyclase-modulating G protein-coupled receptor signalling in the thalidomide mechanism of action.
P365 Identification of predictive factors of AZA/6-MP treatment outcome in paediatric luminal Crohn’s disease: a multicentre study of the paediatric IBD Porto group of ESPGHAN
Authors: LERCHOVA T , Hradsky O , Kulich M , Veres G , Dias J A , Sladek M , Kolacek S , Van Biervliet S , Melek J , Serban D , Winther K , de Meij T , Schwarz J , Kolho K L , Escher J C , Bronsky J 
Published: January 2020

Abstract

Background
According to current guidelines, most paediatric patients in Europe diagnosed with Crohn′s disease (CD) are prescribed long-term immunosuppressive therapy with azathioprine (AZA). This study aimed to develop a predictive model allowing to stratify patients who will not benefit from AZA maintenance treatment and who require a more intensive therapeutic approach early after diagnosis.

Methods
The study was designed to develop a clinical prediction rule using retrospective data analysis from patients included to prospective inception cohort, the EUROKIDS-IBD until 2017. In total, 1190 CD patients using AZA were selected from the registry in 13 European centres. Of these, 441 patients who responded to induction treatment, started AZA treatment within 6 weeks from the time of diagnosis and maintained remission at week 12 were entered into this multicentre study. The primary outcome was time to clinical relapse defined as a necessity of re-induction of remission. A sequence of Cox models was fitted to predict the risk of relapse. Variables appearing to be significant in univariate risk analyses were added to the model one by one and non-significant terms were dropped.

Results
More than 50 % of patients did not experience a clinical relapse within 2 years of AZA treatment (Figure 1). The median time to relapse was 2.11 (CI 1.59–2.46) years. Out of all tested parameters available at the time of diagnosis,8 were predictive in the context of early relapse. Only 4 of these variables, namely centre (p = 0.0009), age (HR = 1.389 95% CI (1.004–1.921), p = 0.047), CRP (HR = 1.504 95% CI (1.116–2.027), p = 0.008) and BMI Z-score (HR = 0.830 95% CI (0.742–0.928), p = 0.001), remained significant in multivariate analyses.

Conclusion
In paediatric CD patients achieving clinical remission after induction treatment at week 12, AZA was effective as maintenance treatment in over 50% of patients for 2 years. Due to low values of HR, the possibility to predict relapse on AZA treatment appears to be limited.
Acknowledgement: This work was supported by the Grant Agency of Charles University in Prague [grant number 364617] and by Ministry of Health, Czech Republic-conceptual development of research organisation, Motol University Hospital, Prague, Czech Republic [00064203].
P376 Real life health care utilisation in paediatric patients with inflammatory bowel disease in the era of biologics
Authors: Tchogna S A , Yang X Y , Deslandres C , Jantchou P 
Published: January 2020

Abstract

Background
The burden associated with the management of paediatric patients with inflammatory bowel disease (IBD) has been rising 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 utilisation.

Methods
The purpose of this study was to assess the health care services utilisation and the associated factors in a prospective cohort of children diagnosed with IBD in Quebec, Canada. 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, hospitalisations and outpatient visits, medications from diagnosis to transition was extracted. We analyzed the healthcare utilisation according to the baseline disease severity (paediatric Crohn’s disease activity index or paediatric ulcerative colitis activity index) at diagnosis, and according to exposition to intravenous biologics.

Results
In total, 144 patients were included in the study [(77 males), CD (N = 98), UC (N = 31) and IBD-U (N = 15); median (interquartile(IQR)) age at diagnosis 15.2 (14.3–16.3) years]. The median (IQR) duration of paediatric follow-up 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 ultrasound1(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-ups 4(0–33). Sixty-four per cent of patients had at least one hospitalisation [median(min–max)1(0–10); median duration 4(0–150 days)] and 35.41% had at least one emergency 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 with 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 (IQR) cumulative days of healthcare utilisation (missing school days) for patients treated with intravenous biologics was 48.5(32.4–67.9) days during paediatric care.

Conclusion
Adolescents with IBD have several healthcare encounters between the diagnosis and transfer to adult care. Disease severity at diagnosis was not related to a higher level of health services utilisation during follow-up. However, treatment with intravenous biologics was associated with a high health service utilisation and school missing during follow-up.
P383 The level of intestinal inflammation and fibrosis in resection specimens after preoperative anti-tumour necrosis factor-α treatment in patients with Crohn’s disease: a comparative pilot study
Authors: Torle J , Dabir P , Korsgaard U , Christiansen J J , Qvist N , El-Hussuna A 
Published: January 2020

Abstract

Background
Strictures are a common complication in Crohn’s disease (CD), which are found in more than 50% of the patients. They are characterised by excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti- TNF-α therapy on the development of fibrosis is not yet fully understood. The aim of the study was to investigate whether the degree of intestinal inflammation and fibrosis correlates with pre-operative anti-TNF-α therapy in patients with Crohn’s disease undergoing bowel resection.

Methods
This is an unblinded, prospective, multicentre cohort pilot study. All adult patients with Crohn’s disease, who underwent elective, laparoscopic or open intestinal resection were included. Pre-operative blood investigations included measurement of TNF- α concentration and specific drug antibodies in addition to the concentration of selected inflammatory cytokines. Three pathologists examined the specimens independently and assessed the degree of inflammation and fibrosis.

Results
Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment pre-operatively. The last dose of anti-TNF-α agents was administered within 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had higher fibrosis score than the controls (p = 0.01). Anti-TNF-α treatment was not associated with an increase in either CD68 or CD163-positive macrophages. There was no significant relationship between time from last anti-TNF-α dose to surgery, and fibrosis score. No significant association between the concentration of major inflammatory cytokines including TNF-α and fibrosis score or degree of inflammation was found.

Conclusion
Patients on anti-TNF-α treatment had higher fibrosis score than the controls.
P389 Post induction infliximab trough levels predict long-term endoscopic remission in paediatric patients with inflammatory bowel disease
Authors: van Hoeve K , Dreesen E , Hoffman I , Ferrante M , Vermeire S 
Published: January 2020

Abstract

Background
Although higher infliximab (IFX) trough levels (TL) have been associated with better outcomes, the ideal predictive sampling time and cut-points to achieve endoscopic remission remain unclear in children with inflammatory bowel disease (IBD). Therefore, we evaluated the pharmacokinetics of IFX during induction to predict long-term outcome of IFX.

Methods
All children with Crohn’s disease (CD) or ulcerative colitis (UC) starting IFX therapy (5 mg/kg at weeks 0–2–6–12) for active luminal disease from May 2017 till May 2019 were followed prospectively. IFX levels were measured by Ridascreen IFX Monitoring ELISA (TL at weeks 2–6–12, peak at weeks 0–2–6 and intermediate at weeks 1–4). IFX levels and cumulative drug exposure (area under the curve (AUC) till week 12) were correlated with the outcome at month 6. Clinical remission was defined as PUCAI/PCDAI &lt;10, biochemical remission as CRP ≤5 mg/l + ESR ≤20 mm/h, endoscopic remission as SES-CD &lt;3 or Mayo endoscopic sub-score = 0 and deep remission if both clinical + endoscopic remission. Results were analysed using Mann–Whitney U-test (presented as median [IQR]).

Results
A total of 252 serum induction levels were included from 32 patients (20 CD and 12 UC; 38% male; median age at start of IFX 13.8 years [11.3–14.9]; 84% on concomitant thiopurines). Clinical remission was achieved in 24 (75%) patients and 18 (56%) were in endoscopic remission (all in deep remission) at month 6. Endoscopic remission at month 6 was associated with significantly higher median IFX TL at week 4 (38.8 µg/ml [24.3–46.0] vs. 23.5 µg/ml [10.5–36.6], p = 0.017), at week 6 (19.9 µg/ml [10.1–26.3] vs. 11.1 µg/ml [3.7–19.9], p = 0.031), at week 12 (9.6 µg/ml [5.5–11.9] vs. 3.5 µg/ml [2.7–7.2], p = 0.004; fig1.) and higher AUC week 0–12 (4574.7 µg*day/ml [3783.0–5160.8] vs. 3722.9 µg*day/ml [3102.2–3991.9], p = 0.008). Median IFX TL at week 12 were significantly higher in children with clinical remission (8.6 µg/ml [5.1–12.0] vs. 4.3 µg/ml [3.1–5.9], p = 0.033), but not for biological remission (6.7 µg/ml [4.0–12.0] vs. 4.3 µg/ml [1.2–7.2], p = 0.250; Figure 2) at month 6. ROC analysis identified an IFX TL at week 12 ≥ 5.0 µg/ml and an AUC weeks 0–12 ≥ 4056.0 µg*day/ml as minimal target to achieve endoscopic remission at mo. 6 (AUROC: 0.796 [95% CI: 0.62–0.97] and AUROC: 0.778 [95% CI: 0.61–0.94], respectively; Figure 3.). Height, haemoglobin and PCDAI score at start of IFX therapy, significantly correlated with week 12 IFX TL.

Conclusion
Adequate IFX exposure during induction in paediatric IBD patients is associated with significantly better clinical, endoscopic and deep remission rates at month 6. Model-informed precision dosing can assist physicians to achieve optimal exposure during induction more precisely (and rapidly) what is essential for an optimal outcome.
P394 Preoperative factors associated with prolonged postoperative in-hospital length of stay in patients with Crohn’s disease undergoing intestinal resection or strictureplasty
Authors: Vinh Luong T , Dich Grandt S , Negoi I , Palubinskas S , El-Hussuna A 
Published: January 2020

Abstract

Background
Postoperative complications might not be accurately registered, leading to weakness in registry data studies.

Aim
To investigate factors that influence postoperative in-hospital length of stay (LOS) in patients with Crohn’s disease (CD) undergoing bowel surgery. Furthermore, the study aimed to evaluate LOS as a surrogate for postoperative outcome.

Methods
A multicentre retrospective cohort study. Inclusion criteria were adult patients with CD who underwent bowel surgery with either anastomosis or stricturoplasty. All timings of surgeries are regardless of the method of access to the abdominal cavities. Patients with stoma were excluded. Demographic data, preoperative medications, previous operations for CD, preoperative sepsis, and operation was recorded. The primary outcome was LOS while the secondary outcome variable was postoperative complications.

Results
449 patients who underwent abdominal surgery for CD were included. 265/449 (59%) were female. Median age was 37 years (IQR =20), median LOS was seven days (IQR =6). Patients with longer LOS had higher rates of re-laparotomy/re-laparoscopy (45/228 (19.7%) vs. 9/219 (4.1%) p = 0.01). In multivariate analysis, age (OR = 1.024 [CI 95% 1.007–1.041], p = 0.005), preoperative intra-abdominal abscess (OR =0.39 [CI 95% 0.185–0.821], p = 0.013), and previous laparotomy/laparoscopy (Or = 0.57 [CI 95% 0.334–0.918], p = 0.021) were associated with prolonged LOS. LOS correlated with postoperative complications after adjustment for age, gender, previous laparotomy/laparoscopy, and preoperative intra-abdominal abscesses (OR = 1.28 [CI 95% 1.199–1.366], p &lt; 0.0001).

Conclusion
Age, preoperative intra-abdominal abscess, and previous laparotomy/laparoscopy significantly prolonged LOS. LOS correlated with postoperative complications and can, therefore, act as a surrogate for the postoperative outcome.
P395 Management of pouch vaginal fistulae in ulcerative colitis: A 35-year experience
Authors: REZA L , Van Praag E , Iqbal N , Twum-Barima C , Hart A , Clark S , Tozer P 
Published: January 2020

Abstract

Background
Pouch vaginal fistulae (PVF) occur following restorative proctocolectomy with an incidence of 6%. The overall rate of pouch failure is 10% but may be as high as 29% with a PVF. PVF can be relatively asymptomatic, with low volume vaginal mucus discharge alone, or can cause considerable morbidity with persistent, passive leakage of faeces and gross perianal excoriation. Management is challenging with a range of reparative techniques reported and no gold standard. Despite a lack of evidence, anti-TNF agents are increasingly used. It is unclear whether there are factors which may predict fistula closure with anti-TNF therapy. The primary aim of fistula therapy should be fistula eradication or amelioration of fistula symptoms without worsening pouch function.

Methods
This is a retrospective analysis of the management of PVF in ulcerative colitis in a tertiary referral centre. Demographic, clinical history and presenting symptoms of fistula including pouch function were collected. Symptomatic burden related to the fistula and the presence or absence of gastrointestinal continuity were assessed.

Results
Fifty patients with PVF were identified between 1984 and 2019 and complete clinical notes were available and analysed for 30 of these. The median age at diagnosis was 36 (range 19–52) years. The median follow-up from pouch creation was 12.5 years. A PVF developed in 30% within 1 year of pouch creation and in 70% after 1 year. In this cohort, 17 (56%) maintained gastrointestinal continuity, of whom 13 were asymptomatic of fistula symptoms (11 after intervention), while 4 were symptomatic but declined intervention. Of the 11 patients who were asymptomatic following treatment, 3 had perianal pouch advancement, 1 had a redo transabdominal pouch, 2 had transvaginal repair, 2 had seton drainage and 3 patients were managed with anti-TNF therapy. Anti-TNF agents were used in 5 patients, 1 of whom was already defunctioned. Three achieved quiescence of symptoms, with 1 requiring pouch excision due to ongoing symptoms. Three patients with poor pouch function prior to anti-TNF therapy noted an improvement in pouch function. Pouch excision or permanent defunctioning was performed in 13 patients (predominantly due to the burden of fistula symptoms rather than poor pouch function).

Conclusion
Around 50% of patients with PVF required pouch excision or permanent defunctioning. The burden of fistula symptoms drove this decision, rather than overall poor pouch function. Anti- TNF therapy improved pouch function and fistula symptoms in a small group of patients but the evidence supporting its use and indications remain limited.
P397 Surveillance in ulcerative colitis: Can we predict the risk for intraepithelial neoplasia?
Authors: Estorninho J , Freire P , Lopes S , Ferreira M , Ferreira M , Portela F , Figueiredo P 
Published: January 2020

Abstract

Background
Ulcerative colitis (UC) has been associated with an increased risk of colorectal cancer (CRC). Although dye spray chromoendoscopy showed superiority to standard colonoscopy in surveillance studies, with the availability of higher-resolution colonoscopes, the utility of chromoendoscopy (CE) has been questioned. We aimed to evaluate the risk of intraepithelial neoplasia (IN) after a high-quality screening colonoscopy (making use of CE or random biopsies (RB) and removing all detected lesions) in a population with longstanding UC and to identify potential risk factors for dysplasia incidence.

Methods
In a previous study, 145 patients with clinically and endoscopic longstanding (≥8 yr) distal/extensive UC without primary sclerosing cholangitis and/or history of IN were prospectively randomised to undergo CE or RB. In this study, after a median follow-up of 5 additional years, we evaluated subsequent IN incidence in these patients, submitted to surveillance colonoscopy. Patients without high-quality surveillance colonoscopy (with good bowel preparation and cecum intubation) using high-definition were excluded.

Results
One hundred and twenty-one patients were included. Nine had removed adenomas with low-grade dysplasia in the index colonoscopy. Now, in surveillance colonoscopy, we detected 9 (7.4%) IN: low-grade dysplasia was found in 8 (6.6%) patients and a colorectal adenocarcinoma in 1 (0.008%) patient. After multivariate analysis, IN was significantly associated with older age (68 vs. 52 years, p &lt; 0.05) and higher disease duration (26 vs. 20 years, p &lt; 0.05). No association was found between IN and previous detection of IN in screening colonoscopy sex, the CE or RB use in index colonoscopy, extent of disease, The presence of pseudopolyps, smoking habits, familial history of CRC or maintenance therapy for UC.

Conclusion
In this study, older patients and higher disease duration were associated with a higher risk of IN in surveillance colonoscopy.
P400 Understanding the impact of TNF-α antagonists on the severity of non-melanoma skin cancer in inflammatory bowel disease and the consequences for therapy
Authors: Townsend C , Khanna R , Wilson A S 
Published: January 2020

Abstract

Background
Non-melanoma skin cancer (NMSC) accounts for at least 40% of all new cancer diagnoses in Canada annually and presents a significant cost to the health care system due to the volume of cases. The incidence of NMSC in patients with inflammatory bowel disease (IBD) is higher when compared with the general population. Generally, in a non-IBD population, the risk of further NMSC progression is low; however, little data exists that highlights differences in the clinical course of patients diagnosed with NMSC who have IBD and are TNF-α antagonist exposed. It is unclear if TNF-α antagonist therapy should be discontinued in this patient population.
Our goal is to determine whether TNF-α antagonist exposure in IBD is associated with a high-risk NMSC presentation at diagnosis, as defined by the National Comprehensive Cancer Network (NCCN) stratification. Our secondary objectives include the presence of positive margins following resection, presence of metastatic disease on initial presentation, the requirement of additional therapy to treat NMSC, number of patients who had TNF-α antagonist therapy discontinued following the diagnosis of NMSC and number of individuals with recurrent NMSC.

Methods
Four hundred and twenty-four IBD patients seen at London Health Sciences Centre were reviewed. We have identified 22 patients who were diagnosed with NMSC. Twelve patients had a pre-NMSC TNF-α antagonist exposure while 10 patients who developed an NMSC and had no TNF-α antagonist exposure prior to NMSC diagnosis.

Results
Preliminary results of the primary outcome demonstrate that 50% (6/12) of patients who have been exposed to TNF antagonist therapy presented with a high-risk NMSC lesion at diagnosis compared with 40% (4/10) who were not exposed (OR 5.16, 95% CI 0.47–57.00; p = 0.181). Preliminary results of the secondary outcomes suggest that 25% (3/12) of patients exposed to TNF-α antagonist had positive margins compared with 0% (0/10) of patients who were not exposed. No patients in either group presented with metastatic disease. Twenty-five per cent (3/12) of patients in the exposed group received more advanced treatment compared with 0% (0/10) in the non-exposed group. Eight per cent (1/12) of patients in the TNF-α antagonist group had their IBD therapy changed from a TNF-α antagonist to an alternative biologic class, and 17% of patients (2/12) in the TNF-α antagonist group had recurrent NMSC lesions.

Conclusion
In conclusion, preliminary results suggest that TNF-α antagonist exposure may be associated with higher risk NMSC lesion at presentation. Further expansion of the sample size is required to explore these hypotheses further.