WallFlex® and Evolution® Duodenal Stents Have Similar Efficacy but Different Safety for Malignant Gastric Outlet Obstruction.

BACKGROUND: The WallFlex® and Evolution® stents are the most widely used duodenal stents, but no study has compared them. AIMS: We aimed to compare the efficacy and safety of WallFlex® and Evolution® stents for malignant gastric outlet obstruction. METHODS: We included all consecutive patients who were treated for malignant gastric outlet obstruction with WallFlex® or Evolution® self-expandable metal uncovered duodenal stents between 2013 and 2020. Multivariable Cox models were performed to assess duodenal stent failure, as defined by gastric outlet obstruction necessitating another duodenal stent. RESULTS: We included 129 patients: 74 received a WallFlex® stent and 55 received an Evolution® stent. The non-failure rate was of 68% (95%CI 55-84) and 65% (95%CI 50-84) at 6 months and of 48% (95%CI 32-73) and 45% (95%CI 27-74) at 1 year, with the WallFlex® and Evolution® stents, respectively. The median time to duodenal stent failure was 10.5 months in the WallFlex® group and 9.3 months in the Evolution® group. The type of duodenal stent was not associated with duodenal stent failure (p logrank = 0.43, adjusted hazard ratio 1.55; 95%CI 0.77-3.14). The overall survival was similar between the two groups (p logrank = 0.92). Three patients had complications due to Evolution® stents; it consisted in dismantled stents that led to hemorrhage in one patient. CONCLUSIONS: WallFlex® and Evolution® duodenal stents had similar efficacy for malignant gastric outlet obstruction. There were more adverse events with Evolution® stents.

Chronic gastrointestinal immune-related adverse events in patients exposed to immune checkpoint inhibitors.

BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICI) cause acute gastrointestinal (GI) immune-related adverse events (IrAEs). We aimed to report and describe chronic GI IrAEs. METHODS: We included consecutive patients addressed to a single center between October 2010 and March 2022 for endoscopic and/or histological GI inflammation persisting at least six months after the last dose of ICI. RESULTS: Among a total of 178 patients addressed for GI IrAE, 14 met the inclusion criteria (8 %). The median follow-up was 13 months after discontinuation of ICI. The most common symptom was watery diarrhea (54 %). Ten (77 %) patients had colonic involvement and three patients (21 %) had ileal involvement. Ten patients (77 %) had inflammatory lesions, two patients (15 %) had fistulas and one patient had (8 %) a stricture. All patients had lymphoplasmacytic infiltrate and basal plasmacytosis, and seven (54 %) had crypt distortions. Nine patients (69 %) received medical therapy, including five patients treated with vedolizumab, two patients (15 %) underwent intestinal resection. At the last follow-up, seven of the 13 patients were receiving maintenance therapy. Endoscopic lesions persisted one year after discontinuing ICI in 4/6 patients, and two years after discontinuation in 3/4 patients. CONCLUSIONS: Chronic GI IrAEs exist after ICI use.

Severe colitis in patients with melanoma treated with BRAF/MEK inhibitors.

BACKGROUND AND AIMS: Dual blockade of BRAF and MEK kinases is a standard of care for metastatic V600E/K BRAF mutant melanoma. This study reports the first systematic description of colitis due to BRAF and MEK inhibitors. METHODS: We studied consecutive patients with melanoma, treated with BRAF and MEK inhibitors, who had colitis requiring hospitalisation. Electronic files were studied; endoscopic biopsies and colectomy specimens were read centrally. RESULTS: Between January 2021 and March 2022, nine women and one man, aged 50-90 years, were studied. Nine patients received encorafenib and binimetinib; one patient received dabrafenib and trametinib. The main symptoms were diarrhoea, haematochezia, abdominal pain and intestinal obstruction. Blood tests showed anaemia, increased CRP and low serum albumin levels in most patients. All patients had ulcerations of the right colon with (2/10) or without (8/10) stenosis of the ileocecal valve, and 4/10 patients also had ulcerations distal to the right colon. Histopathological findings were suggestive of ischaemia and mild inflammation. Nine of the 10 patients discontinued BRAF/MEK inhibitors. Drugs were reintroduced in four patients, three of whom had a severe relapse of diarrhoea. Two patients required surgery and underwent intestinal resection. One patient died of enterocolitis. CONCLUSION: BRAF/MEK inhibitors can induce severe colitis characterised by ulcerations of the right colon.

Notch inhibitors induce diarrhea, hypercrinia and secretory cell metaplasia in the human colon.

In humans, inhibition of Notch oncogenic signaling leads to tumor regression. Preclinical studies indicate that Notch signaling contributes to the maintenance of intestinal homeostasis. Here, we sought to describe the intestinal effects of a first-in-human Notch inhibitor in an indication of refractory cancer. Between 2014 and 2017, adult patients treated for refractory cancer with the novel Notch inhibitor LY3039478 and who had grade ≥ 2 diarrhea were referred to the gastroenterology department of a tertiary hospital in the Paris region of France. Eleven patients (median (range) age: 72 (29-83)) were included in the study. All patients had advanced cancer: adenoid cystic carcinoma (n=3, 27 %), sarcoma (n=3, 27 %), and other types (n=5, 46 %). In all cases, digestive tract endoscopy revealed abundant mucus in the intestinal lumen, and digestive tract biopsies showed an abnormally low proportion of enterocytes and marked elevation of the proportion of pseudostratified goblet cells. Microscopic inflammation was seen in colon biopsies from 2 of the 11 patients (18 %). The clinical, endoscopic and histological abnormalities were dependent on the dose of Notch inhibitor. All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). Likewise, the median time interval between discontinuation and resolution of the histological abnormalities was 7 days (1-10). Blocking Notch signaling induces secretory cell metaplasia of the intestinal epithelium, which in turn leads to transient diarrhea. Our results confirm the role of Notch signaling in intestinal homeostasis in humans.

Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis: A GETAID cohort.

BACKGROUND: Up to 25% of patients with ulcerative colitis (UC) will require hospitalization for severe flare. In patients hospitalised for severe flare, who previously experienced multiple drug failures, including steroids and anti-TNF agents, new quick-acting medical options are needed. Tofacitinib is effective in refractory UC and has a rapid onset of action. AIM: To evaluate effectiveness and safety of tofacitinib as rescue therapy in patients hospitalised for UC flare. METHODS: We conducted an observational and multicentre study with both retrospective and prospective collections in 14 GETAID centres. The primary objective was to assess the survival without colectomy following tofacitinib initiation in patients hospitalised for a UC flare. We determined rates of clinical response, clinical remission, and steroid-free clinical remission at week 6 and week 14 and safety. RESULTS: Fifty-five patients were included (49 with prior infliximab failure and 19 previously exposed to ciclosporin). With a median follow-up of 6.5 months (interquartile range [IQR] [3-12.3]), rate of colectomy-free survival was estimated at 78.9% (95 CI [68.5-90.9]) and 73.6% (95 CI [61.9-87.3]) at 3 and 6 months, respectively. Rates of clinical response, clinical remission and steroid-free clinical remission were 60%, 45.5% and 37.5% at week 6 and 41.8%, 34.5% and 32.7% at week 14. Regarding safety, no death was observed, three patients withdrew tofacitinib due to adverse events. Two herpes zoster infections occurred in patients aged over 60 years old. No venous thrombotic or major adverse cardiovascular events occurred. CONCLUSION: Tofacitinib appears as a promising option in patients hospitalised with a UC flare but needs further validation in controlled trials.

Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease.

BACKGROUND: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear. AIM: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD METHODS: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models. RESULTS: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06-2.19; P = 0.023), 2.23 (95% CI: 1.79-2.79; P < 0.001) and 3.71 (95% CI: 2.30-6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03-2.81; P = 0.039) and 2.49 (95% CI: 1.39-4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48-1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale. CONCLUSIONS: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.