BACKGROUND & AIMS:Severe alcohol-related hepatitis (AH) has high short-term mortality, and corticosteroid therapy is recommended in the absence of contraindications. However, its benefit in patients with early spontaneous bilirubin improvement remains unknown. We aim at determining whether corticosteroid therapy improves survival compared with placebo in this specific population. METHODS:In this multicenter, randomized, placebo-controlled trial conducted in 10 Belgian hospitals (from February 2018 to May 2024), patients aged ≥18 yr with biopsy-proven severe AH and spontaneous bilirubin decline >10% between admission and Day 5-10 were randomized 1:1 to methylprednisolone 32 mg daily or placebo for 28 days. The primary outcome was 90-day survival; other outcomes included 30-day survival and cumulative incidence of infection at 90 days. RESULTS:We analyzed 69 (49%) of the 140 planned patients (38 corticosteroid, 31 placebo). Baseline characteristics were well balanced. At 90 days, survival was 79% (95% CI 67-93%) vs. 83% (95% CI 70-98%) (hazard ratio 1.19, 95% CI 0.39-3.63, p = 0.76). Eight deaths occurred in the corticosteroid arm vs. five in the placebo arm. At 30 days, survival was 95% vs. 94% (p = 0.83). Cumulative incidence of infection at 90 days was 47% vs. 34% (subdistribution hazard ratio 1.55, 95% CI 0.72-3.34, p = 0.26). Lille score was an independent predictor of 90-day mortality. CONCLUSIONS:In patients with severe AH and early spontaneous bilirubin improvement, corticosteroid therapy was not associated with improved survival, but the underpowered trial cannot exclude a benefit. A short observation period after admission may help identify patients who can be managed without corticosteroids. IMPACT AND IMPLICATIONS:Corticosteroid therapy is recommended for patients with severe alcohol-related hepatitis (AH), but whether this benefit extends to those who show early spontaneous improvement in bilirubin after admission was previously unknown. In this multicenter, randomized, placebo-controlled trial, corticosteroid therapy was not associated with improved 90-day or 30-day survival in patients with severe, biopsy-proven AH and a spontaneous bilirubin decline of >10% within 5-10 days of admission. Corticosteroids were associated with a numerically higher, though not statistically significant, risk of infection. These findings are most relevant to hepatologists and other clinicians managing severe AH, and to researchers designing future AH trials, as they identify a subgroup in whom the benefit of corticosteroids is uncertain. They support a risk-stratified approach in which a brief observation period after admission-incorporating bilirubin trend, infection screening, and liver biopsy-may help identify patients with a relatively favorable prognosis who can be spared corticosteroid therapy and its associated risks. However, because the trial was stopped early after enrolling only 69 of the 140 planned patients, it was underpowered, and a modest survival benefit of corticosteroids cannot be excluded. Therefore, these results should not be interpreted as definitive evidence against corticosteroid use in this population. Larger, adequately powered studies are required to validate these findings before informing clinical guidelines or being generalized to broader patient populations. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov (NCT03160651), EudraCT number: 2016-005136-16.

Background: Keratin 7 positive (K7+) cells are considered to be activated in case of impaired hepatocyte replication. Their exact role and their interaction with hepatocytes and macrophages also implicated in liver regeneration remain poorly characterized in humans. The aim of this study is to evaluate hepatocyte, K7+ cells and macrophage populations in severe alcohol-related steatohepatitis (sASH) and to link them with liver injury and patients' outcomes. Methods: Immunohistochemical and morphometric studies for total K7+ cells, macrophages (CD68+ cells), proliferative hepatocytes (Ki67+ hepatocytes) and proliferative K7+ cells (double K7+ and Ki67+) were performed on liver biopsies of patients with sASH recruited prospectively in 16 different centres. Patients were divided into improvers or non-improvers, according to mortality and model for end-stage liver disease (MELD) score change at 3 months. Results: Fifty-seven cases were included for histological and morphometrical assessment. Liver total K7+ cell expansion was positively correlated to the severity of the disease evaluated by the MELD score. A proportion of these K7+ cells were proliferating. The number of proliferating K7+ cells was less than the number of proliferating hepatocytes. Increased hepatocyte replication was correlated to a higher proliferative K7+ cell count. A higher number of macrophages was associated with a higher proliferation of both hepatocytes and K7+ cells. No difference of total K7+ cells, proliferative K7+ cells, proliferative hepatocytes or macrophages was observed between improvers and non-improvers. Conclusions: In biopsy-proven cases of sASH, proliferation of hepatocytes and K7+ cells occurs in parallel. This could suggest that liver progenitor cells begin to replicate even in the absence of massive hepatocyte senescence in humans, or that proliferating progenitor cells are capable of giving rise to hepatocytes with replicative skills. This is associated with macrophagic expansion, which is therefore considered beneficial. However, in this severe, life-threatening disease, these mechanisms remain insufficient to improve patient prognosis.

OBJECTIVE:Hemin, a heme oxygenase 1 activator has shown efficacy in the prevention and treatment of acute pancreatitis in mouse models. We conducted a randomized controlled trial (RCT) to assess the protective effect of Hemin administration to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in patients at risk.METHODS:In this multicenter, multinational, placebo-controlled, double-blind RCT, we assigned patients at risk for PEP to receive a single intravenous dose of Hemin (4 mg/kg) or placebo immediately after ERCP. Patients were considered to be at risk on the basis of validated patient- and/or procedure-related risk factors. Neither rectal NSAIDs nor pancreatic stent insertion were allowed in randomized patients. The primary outcome was the incidence of PEP. Secondary outcomes included lipase elevation, mortality, safety, and length of stay.RESULTS:A total of 282 of the 294 randomized patients had complete follow-up. Groups were similar in terms of clinical, laboratory, and technical risk factors for PEP. PEP occurred in 16 of 142 patients (11.3%) in the Hemin group and in 20 of 140 patients (14.3%) in the placebo group (p = 0.48). Incidence of severe PEP reached 0.7% and 4.3% in the Hemin and placebo groups, respectively (p = 0.07). Significant lipase elevation after ERCP did not differ between groups. Length of hospital stay, mortality and severe adverse events rates were similar between groups.CONCLUSION:We failed to detect large improvements in PEP rate among participants at risk for PEP who received IV hemin immediately after the procedure compared to placebo.TRIAL REGISTRATION NUMBER:ClinicalTrials.gov number, NCT01855841).

BACKGROUND & AIMS:Severe alcoholic hepatitis (AH) is a life-threatening disease for which adequate oral nutritional support is recommended. We performed a randomized controlled trial to determine whether the combination of corticosteroid and intensive enteral nutrition therapy is more effective than corticosteroid therapy alone in patients with severe AH.METHODS:We enrolled 136 heavy consumers of alcohol (age, 18-75 y) with recent onset of jaundice and biopsy-proven severe AH in our study, performed at 18 hospitals in Belgium and 2 in France, from February 2010 through February 2013. Subjects were assigned randomly (1:1) to groups that received either intensive enteral nutrition plus methylprednisolone or conventional nutrition plus methylprednisolone (controls). In the intensive enteral nutrition group, enteral nutrition was given via feeding tube for 14 days. The primary end point was patient survival for 6 months.RESULTS:In an intention-to-treat analysis, we found no significant difference between groups in 6-month cumulative mortality: 44.4% of patients died in the intensive enteral nutrition group (95% confidence interval [CI], 32.2%-55.9%) and 52.1% of controls died (95% CI, 39.4%-63.4%) (P = .406). The enteral feeding tube was withdrawn prematurely from 48.5% of patients, and serious adverse events considered to be related to enteral nutrition occurred in 5 patients. Regardless of group, a greater proportion of patients with a daily calorie intake less than 21.5 kcal/kg/day died (65.8%; 95% CI, 48.8-78.4) than patients with a higher intake of calories (33.1%; 95% CI, 23.1%-43.4%) (P < .001).CONCLUSIONS:In a randomized trial of patients with severe AH treated with corticosteroids, we found that intensive enteral nutrition was difficult to implement and did not increase survival. However, low daily energy intake was associated with greater mortality, so adequate nutritional intake should be a main goal for treatment. ClinicalTrials.gov number: NCT01801332.

Saline-filled intragastric balloons (IB) may be inserted for 6 months to promote weight loss. We aimed to assess potential benefits of repeating IB therapy.

Available estimates of the incidence and type of complications during pediatric EGD are inconsistent.Our objective was to determine the frequency and determinants of immediate complications during EGD in children.We conducted a crosssectional database study that involved 13 pediatric facilities that use the PEDS-CORI (Pediatric Endoscopy Database System Clinical Outcomes Research Initiative).We identified complications (recorded shortly after the procedure) and analyzed their occurrence with respect to procedure indication, American Society of Anesthesiologists (ASA) class, sex, age, anesthesia type, and unplanned interventions.We analyzed 10,236 procedures performed in 9234 patients.Immediate complications were reported in 239 procedures (2.3%; 95% confidence interval 2.0%-2.6%).The most common complications were hypoxia (157 [1.5%]) and bleeding (28 [0.3%]).Complication rates were significantly higher in the youngest age group, highest ASA class, female gender, intravenous (IV) sedation group, and in the presence of a fellow.The overall immediate complication rate of pediatric EGD is 2.3%.All complications were nonfatal, and most were hypoxia related (157/239 [66%]) and reversible.Young age, higher ASA class, female sex, and IV sedation are risk factors for developing complications.

BACKGROUND:In chronic pancreatitis, obstruction of the main pancreatic duct (MPD) may contribute to the pathogenesis of pain. Pilot studies suggest that extracorporeal shock wave lithotripsy (ESWL) alone relieves pain in calcified chronic pancreatitis.AIM:To compare ESWL alone with ESWL and endoscopic drainage of the MPD for treatment of pain in chronic pancreatitis.SUBJECTS:Patients with uncomplicated painful chronic pancreatitis and calcifications obstructing the MPD.METHODS:55 patients were randomised to ESWL alone (n = 26) or ESWL combined with endoscopy (n = 29).RESULTS:2 years after trial intervention, 10 (38%) and 13 (45%) patients of the ESWL alone and ESWL combined with endoscopy group, respectively, had presented pain relapse (primary outcome) (OR 0.77; 95% CI 0.23 to 2.57). In both groups, a similar decrease was seen after treatment in the MPD diameter (mean decrease 1.7 mm; 95% CI 0.9 to 2.6; p<0.001), and in the number of pain episodes/year (mean decrease, 3.7; 95% CI 2.6 to 4.9; p<0.001). Treatment costs per patient were three times higher in the ESWL combined with endoscopy group compared with the ESWL alone group (p = 0.001). The median delay between the onset of chronic pancreatitis and persistent pain relief for both groups was 1.1 year (95% CI 0.7 to 1.6), as compared with 4 years (95% CI 3 to 4) for the natural history of chronic pancreatitis in a reference cohort (p<0.001).CONCLUSIONS:ESWL is a safe and effective preferred treatment for selected patients with painful calcified chronic pancreatitis. Combining systematic endoscopy with ESWL adds to the cost of patient care, without improving the outcome of pancreatic pain.

In colon cancer, endothelial cell selectins can promote tumor cell attachment via interactions with sialylated Lewis antigens present at the surface of tumor cells, thereby facilitating tumor cell arrest and transmigration into the extravascular space. However, it is not known whether Lewis antigens interact with colon tumor cells and modify their migration. Our aim was to detect the presence of binding sites on human tumor cells for Lewisa/x antigens and their sialylated derivatives in vitro and in vivo and to analyze their influence on migration of colon cancer cells. The immunocytochemical and histochemical levels of expression of the four Lewis antigens were quantitatively determined in four human colon cancer cell lines and in in vivo nude mice xenografts. The levels of expression of specific binding sites for these sugar epitopes were determined by synthetic neoglycoconjugates. The influence of binding of these carbohydrate ligands on cancer cell migration was quantitatively evaluated by computer-assisted phase-contrast videomicroscopy performed on Matrigel culture supports either left uncoated or coated with neoglycoconjugate presenting synthetic Lewisa, sialyl Lewisa, Lewisx, or sialyl Lewisx antigens. The influence of the calcium concentration in the culture medium on the Lewis antigen–mediated effects was checked. Human colon cancer cells expressed significant amounts of specific binding sites detected by the synthetic probes in addition to the oligosaccharide epitopes. The expression levels differed considerably between the four cell lines and between in vitro and in vivo specimens. Cell migration analysis revealed that the four Lewis antigens markedly decreased the levels of migration of the HCT-15 and LoVo cancer cells. This effect depends on the calcium concentration in the culture medium. Binding sites for Lewis epitopes are present on colon cancer cells. The functional relevance of these sites is indicated by the negative influence on cell migration of a matrix containing the oligosaccharides as ligand parts.