The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red +, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis. </p

The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts.

Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red +, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis

First case of endoscopic ultrasound-guided gastrojejunal anastomosis for duodenal stricture in refractory Crohn's disease: a bridge toward inflammation control.

Endoscopic ultrasonography-guided gastrojejunal anastomosis (EUS-GJA) was developed in 2015 using a lumen-apposing metal stent (LAMS) [1] [2]. Its application was described for malignant bowel obstruction and a few cases of benign obstruction [3] [4]. Crohn’s disease is an inflammatory bowel disease that could induce inflammatory or fibrotic bowel strictures, the management of which includes medical therapy, endoscopic dilation or surgical resection [5]. We report a case of duodenal stricture in severe Crohn’s disease and short bowel syndrome. [...

Management of immune checkpoint inhibitor in patients with cancer and pre-existing inflammatory bowel disease: Recommendations from the GETAID

International audienceBackground and aims: There is no consensus on the management of immune checkpoint inhibitor (ICI) for treating cancer in patients with pre-existing inflammatory bowel disease (IBD). The Groupe d'Étude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) aimed to provide recommendations on this topic.Methods: A dedicated working group performed a comprehensive expert-based review of the literature, generated clinical key question and shaped recommendations that were further voted for approval by the educational and scientific committees of the GETAID. Using consensus methods, treatment modalities were defined by vote.Results: Majority of patients with IBD in clinical remission can be treated with ICI after cancer diagnosis. The rate of relapse or immune-related diarrhoea or colitis upon ICI treatment is up to 39.8% and is maximal with ICI combination therapy compared to monotherapies. When starting ICI in a patient with IBD, it is recommended to assess disease activity and pursue ongoing maintenance therapy. In case of relapse or immune-related diarrhoea or colitis upon ICI treatment, treatment depends on grading of diarrhoea or colitis and may include corticosteroid therapy, infliximab and/or vedolizumab.Conclusions: In the present publication, we provided recommendations, which may assist gastroenterologists, haematologists, and oncologists for a better management of patients with pre-existing IBD before and during cancer treatment with ICI

Real‐world comparison of effectiveness between tofacitinib and vedolizumab in patients with ulcerative colitis exposed to at least one anti‐ TNF agent

International audienceBackground: Data comparing tofacitinib and vedolizumab in ulcerative colitis (UC) are lacking.Aims: To compare the effectiveness of tofacitinib and vedolizumab in patients with UC who had prior exposure to anti-TNF therapy METHODS: In this multicentre study, we included consecutive patients with UC ≥18 years old with partial Mayo score >2 and prior anti-TNF exposure, who started tofacitinib or vedolizumab between January 2019 and June 2021. Comparisons were performed using propensity score analyses (inverse probability of treatment weighting).Results: Overall, 126 and 178 patients received tofacitinib and vedolizumab, respectively. Intensified induction (vedolizumab infusion at week 10 or tofacitinib 10 mg b.d until week 16) was performed in 28.5% and 41.5% of patients, respectively. After propensity-score analysis, corticosteroid-free clinical remission (partial Mayo score ≤2) was achieved at week 16 in 45.1% and 40.2% of patients receiving tofacitinib and vedolizumab, respectively (aOR = 0.82 [0.35-1.91], p = 0.64). Endoscopic improvement (corticosteroid-free clinical remission and endoscopic Mayo score ≤1) (aOR = 0.23[0.08-0.65], p = 0.0032) and histological healing (endoscopic improvement + Nancy histological index ≤1) (13.4% vs 3.2%, aOR = 0.21[0.05-0.91], p = 0.023) were higher at week 16 in patients treated with tofacitinib. No factor was predictive of tofacitinib effectiveness. At least one primary failure to a biologic (OR = 0.46[0.22-0.99], p = 0.049), partial Mayo score >6 (OR = 0.39[0.17-0.90], p = 0.029) and CRP level > 30 mg/L at baseline (OR = 0.08[0.01-0.85], p = 0.036) were associated with vedolizumab failure.Conclusion: Tofacitinib and vedolizumab are effective in UC after failure of anti-TNF agents. However, tofacitinib seems more effective, especially in severe disease and primary failure to biologics

Preoperative Predictors of Neoplasia in Patients Undergoing Small Bowel Resection for Complicated Crohn’s Disease: A Multicentre Case-Control Study

Crohn’s disease (CD) is associated with an increased risk of small bowel neoplasia (SBN). We aimed to assess preoperative predictors of SBN in CD patients. We conducted a retrospective case-control study including CD patients who underwent surgery: cases were diagnosed with SBN on histopathological analysis and controls had no neoplasia. Preoperative cross-sectional imaging was reviewed by a panel of blinded expert radiologists. Fifty cases were matched to one hundred and fifty consecutive controls. In multivariable analysis, predictors of SBN were age ≥ 50 years (OR = 28, 95% CI = 5.05–206), median CD duration ≥ 17.5 years (OR = 4.25, 95% CI = 1.33–14.3), and surgery for stricture (OR = 5.84, 95% CI = 1.27–35.4). The predictors of small bowel adenocarcinoma were age ≥ 50 years (OR = 5.14, 95% CI = 2.12–12.7), CD duration ≥ 15 years (OR = 5.65, 95% CI = 2.33–14.3), and digestive wall thickening > 8 mm (OR = 3.79, 95% CI = 1.45–11.3). A predictive score based on the aforementioned factors was constructed. Almost 73.7% of patients with a high score had SBA. Old age, long small bowel CD duration, and stricture predicted the presence of SBN, particularly adenocarcinoma when patients have digestive wall thickening > 8 mm on preoperative imaging

Effectiveness and safety of ustekinumab maintenance therapy in 103 patients with ulcerative colitis: a GETAID cohort study

International audienceBackground Phase III trials have demonstrated the efficacy and safety of ustekinumab in ulcerative colitis (UC), but few real-life long-term data are currently available. Aims To assess the real-world effectiveness and safety of ustekinumab in patients with UC. Methods From January to September 2019, all consecutive patients with active UC treated with ustekinumab in a GETAID centre were included. Patients were evaluated at week 52. Remission was defined as a partial Mayo Clinic score &lt;= 2. Results We included 103 patients with UC (62 men; mean age: 41.2 +/- 16.2 years; 52% pancolitis E3) with an insufficient response to immunosuppressants, anti-TNFs and/or vedolizumab. At week 52, 45 (44%) patients had discontinued ustekinumab mainly due to lack of effectiveness (n = 41). The cumulative probabilities of ustekinumab persistence were 96.1%, 81.6%, 71.7% and 58.4% after 3, 6, 9 and 12 months respectively. The overall steroid-free clinical remission rate at week 52 was 32% of whom 71% had subscores of null for rectal bleeding and stool frequency. Ten patients underwent colectomy within a median of 6.7 [4.3-10.6] months. Adverse effects were observed in 15 (16.9%) patients; 4 (4.5%) were severe, including one patient who died from a myocardial infarction. Conclusion After 52 weeks, over one-half of patients with refractory UC were still treated by ustekinumab and one-third were in steroid-free clinical remission

Effectiveness and safety of ustekinumab induction therapy for 103 patients with ulcerative colitis: a GETAID multicentre real-world cohort study

International audienceBackground Phase III trials have demonstrated the efficacy and safety of ustekinumab in moderate-to-severe ulcerative colitis (UC), but few real-world data are currently available. Aim To assess short-term effectiveness and safety of ustekinumab in patients with UC. Methods From January to September 2019, all patients with UC treated with ustekinumab in 20 French GETAID centres were retrospectively included. The primary outcome was steroid-free clinical remission (partial Mayo Clinic score 1. Results Among the 103 patients included, 70% had been previously exposed to >= 2 anti-TNF agents and 85% to vedolizumab. At weeks 12-16, steroid-free clinical remission and clinical remission rates were 35.0% and 39.8% respectively; the absence of rectal bleeding with normal stool frequency was noted in 19.4% of patients. Two patients discontinued ustekinumab before the week 12-16 visit and underwent surgery. In multivariable analysis, a partial Mayo Clinic score >6 at inclusion (18.6% vs 46.7%, P = 0.003) and a history of both exposure to anti-TNF and vedolizumab therapies (27.3% vs 80.0%, P = 0.001) were negatively associated with steroid-free clinical remission at weeks 12-16. Adverse events occurred in 7.8% of patients and serious adverse events in 3.9% of patients. Conclusion In a cohort of highly refractory patients with UC with multiple prior drug failures, ustekinumab provided steroid-free clinical remission in one-third of cases at weeks 12-16. Clinical severity and previous use of anti-TNF and vedolizumab therapies were associated with ustekinumab failure at weeks 12-16

Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis

Objective In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B 5 , a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. Design We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. Results VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. Conclusion The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B 5-driven metabolism should improve mucosal healing and might increase the efficacy of antiinflammatory therapy