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In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. In the safety study, which included 68,038 infants, the rates of intussusception were similar in the vaccine and placebo groups (relative risk, 0.8; 95 percent confidence interval, 0.3 to 1.8). In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants and young children worldwide. More than 2 million hospitalizations and nearly half a million deaths are attributed to this infection annually. 1 , 2 The strategy of preventing rotavirus through vaccination derives from studies demonstrating that wild-type rotavirus infection induces immunity against subsequent rotavirus gastroenteritis. 3 – 6 Primary rotavirus infection provides substantial protection against gastroenteritis caused by the same serotype and against severe disease regardless of serotype. The four most prevalent serotypes, which account for more than 80 percent of cases of human rotavirus disease worldwide, are G1P[8], G2P[4], . . .

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Objective To compare the predictive accuracy and clinical utility of five risk scoring systems in the assessment of patients with upper gastrointestinal bleeding.Design International multicentre prospective study.Setting Six large hospitals in Europe, North America, Asia, and Oceania.Participants 3012 consecutive patients presenting over 12 months with upper gastrointestinal bleeding.Main outcome measures Comparison of pre-endoscopy scores (admission Rockall, AIMS65, and Glasgow Blatchford) and post-endoscopy scores (full Rockall and PNED) for their ability to predict predefined clinical endpoints: a composite endpoint (transfusion, endoscopic treatment, interventional radiology, surgery, or 30 day mortality), endoscopic treatment, 30 day mortality, rebleeding, and length of hospital stay. Optimum score thresholds to identify low risk and high risk patients were determined.Results The Glasgow Blatchford score was best (area under the receiver operating characteristic curve (AUROC) 0.86) at predicting intervention or death compared with the full Rockall score (0.70), PNED score (0.69), admission Rockall score (0.66, and AIMS65 score (0.68) (all P<0.001). A Glasgow Blatchford score of ≤1 was the optimum threshold to predict survival without intervention (sensitivity 98.6%, specificity 34.6%). The Glasgow Blatchford score was better at predicting endoscopic treatment (AUROC 0.75) than the AIMS65 (0.62) and admission Rockall scores (0.61) (both P<0.001). A Glasgow Blatchford score of ≥7 was the optimum threshold to predict endoscopic treatment (sensitivity 80%, specificity 57%). The PNED (AUROC 0.77) and AIMS65 scores (0.77) were best at predicting mortality, with both superior to admission Rockall score (0.72) and Glasgow Blatchford score (0.64; P<0.001). Score thresholds of ≥4 for PNED, ≥2 for AIMS65, ≥4 for admission Rockall, and ≥5 for full Rockall were optimal at predicting death, with sensitivities of 65.8-78.6% and specificities of 65.0-65.3%. No score was helpful at predicting rebleeding or length of stay.Conclusions The Glasgow Blatchford score has high accuracy at predicting need for hospital based intervention or death. Scores of ≤1 appear the optimum threshold for directing patients to outpatient management. AUROCs of scores for the other endpoints are less than 0.80, therefore their clinical utility for these outcomes seems to be limited.Trial registration Current Controlled Trials ISRCTN16235737.

ObjectiveAcute non-variceal upper gastrointestinal bleeding (NVUGIB) is managed by standard endoscopic combination therapy, but a few cases remain difficult and carry a high risk of persistent or recurrent bleeding. The aim of our study was to compare first-line over-the-scope-clips (OTSC) therapy with standard endoscopic treatment in these selected patients.DesignWe conducted a prospective, randomised, controlled, multicentre study (NCT03331224). Patients with endoscopic evidence of acute NVUGIB and high risk of rebleeding (defined as complete Rockall Score ≥7) were included. Primary endpoint was clinical success defined as successful endoscopic haemostasis without evidence of recurrent bleeding.Results246 patients were screened and 100 patients were finally randomised (mean of 5 cases/centre and year; 70% male, 30% female, mean age 78 years; OTSC group n=48, standard group n=52). All but one case in the standard group were treated with conventional clips. Clinical success was 91.7% (n=44) in the OTSC group compared with 73.1% (n=38) in the ST group (p=0.019), with persistent bleeding occurring in 0 vs 6 in the OTSC versus standard group (p=0.027), all of the latter being successfully managed by rescue therapy with OTSC. Recurrent bleeding was observed in four patients (8.3%) in the OTSC group and in eight patients (15.4%) in the standard group (p=0.362).ConclusionOTSC therapy appears to be superior to standard treatment with clips when used by trained physicians for selected cases of primary therapy of NVUGIB with high risk of rebleeding. Further studies are necessary with regards to patient selection to identify subgroups benefiting most from OTSC haemostasis.Trial registration number NCT03331224.

ObjectiveLimited data are available on the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis (PVT). This study aimed to compare transjugular intrahepatic portosystemic shunt (TIPS) with covered stents versus endoscopic band ligation (EBL) plus propranolol for the prevention of variceal rebleeding among patients with cirrhosis and PVT.DesignConsecutive cirrhotic patients (94% Child-Pugh class A or B) with PVT who had variceal bleeding in the past 6 weeks were randomly assigned to TIPS group (n=24) or EBL plus propranolol group (EBL+drug, n=25), respectively. Primary endpoint was variceal rebleeding. Secondary endpoints included survival, overt hepatic encephalopathy (OHE), portal vein recanalisation and rethrombosis, other complications of portal hypertension and adverse events.ResultsDuring a median follow-up of 30 months in both groups, variceal rebleeding was significantly less frequent in the TIPS group (15% vs 45% at 1 year and 25% vs 50% at 2 years, respectively; HR=0.28, 95% CI 0.10 to 0.76, p=0.008), with a significantly higher portal vein recanalisation rate (95% vs 70%; p=0.03) and a relatively lower rethrombosis rate (5% vs 33%; p=0.06) compared with the EBL+drug group. There were no statistically significant differences in survival (67% vs 84%; p=0.152), OHE (25% vs 16%; p=0.440), other complications of portal hypertension and adverse events between groups.ConclusionCovered TIPS placement in patients with PVT and moderately decompensated cirrhosis was more effective than EBL combined with propranolol for the prevention of rebleeding, with a higher probability of PVT resolution without increasing the risk of OHE and adverse effects, but this benefit did not translate into improved survival.Trial registration numberClinicalTrials.gov: NCT01326949.

Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, infection, and patient-important bleeding. A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

BackgroundProphylactic application of a haemostatic gel to the resection field may be an easy way to prevent delayed bleeding, a frequent complication after endoscopic mucosal resection (EMR).ObjectiveWe aimed to evaluate if the prophylactic application of a haemostatic gel to the resection field directly after EMR can reduce the rate of clinically significant delayed bleeding events.DesignWe conducted a prospective randomised trial of patients undergoing hot-snare EMR of flat lesions in the duodenum (≥10 mm) and colorectum (≥20 mm) at 15 German centres. Prophylactic clip closure was not allowed, but selective clipping or coagulation could be used prior to randomisation to treat intraprocedural bleeding or for prophylactic closure of visible vessels. Patients were randomised to haemostatic gel application or no prophylaxis. The primary endpoint was delayed bleeding within 30 days.ResultsThe trial was stopped early due to futility after an interim analysis. The primary endpoint was analysed in 232 patients (208 colorectal, 26 duodenal). Both groups were comparable in age, sex, comorbidities and lesion characteristics. Preventive measures, such as selective clipping or coagulation, were applied prior to randomisation in 51.9% of cases, with no difference between groups. Delayed bleeding occurred in 14 cases (11.7%; 95% CI 7.1% to 18.6%) after Purastat and in 7 cases (6.3%; 95% CI 3.1% to 12.3%) in the control group (p=0.227), with no difference between colorectal and duodenal subgroups.ConclusionThe application of a haemostatic gel following EMR of large flat lesions in the duodenum and colorectum does not reduce the rate of delayed bleeding.

Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).

BackgroundProphylactic clip closure after endoscopic mucosal resection reduces delayed bleeding in large and proximal colon lesions; however, evidence regarding its effectiveness in colorectal endoscopic submucosal dissection (ESD) is lacking.ObjectiveTo compare clinically significant delayed bleeding rates between a clip closure and a control group for flat and sessile 20–50 mm colorectal polyps following ESD.DesignA multicentre randomised controlled trial conducted at four Japanese institutions randomly assigned patients to closure or non-closure groups. Significant postprocedural bleeding (haematochezia) was classified as severe (requiring endoscopic haemostasis or blood transfusion in patients with haemoglobin levels <70 g/L or haemorrhagic shock) or mild.ResultsThe closure and control groups comprised 150 and 149 cases in the intention-to-treat (ITT) analysis and 142 and 141 cases in the per-protocol (PP) analysis, respectively. Rates of complete clip closure were 88.7% (ITT) and 93.0% (PP). The ITT analysis revealed delayed bleeding rates of 6.7% and 20.1% (OR: 0.28; 95% CI: 0.13 to 0.60; p<0.001; absolute risk difference (ARD): 13.5%; 95% CI: 5.6% to 20.9%) and severe delayed bleeding rates of 1.3% and 8.7% (OR: 0.14; 95% CI: 0.03 to 0.64; p=0.003; ARD: 7.4%; 95% CI: 2.2% to 12.4%) in the closure and control groups, respectively. These differences were confirmed in the PP analysis. Delayed perforation was not observed, and the post-ESD coagulation syndrome rate was not significantly different between the two groups. Multivariate logistic regression analyses identified prophylactic clip closure as a significant independent preventive factor for both delayed bleeding (OR: 0.22; 95% CI: 0.08 to 0.50; p<0.001) and severe delayed bleeding (OR: 0.22; 95% CI: 0.05 to 0.76; p=0.015).ConclusionsProphylactic clip closure, successfully achieved in approximately 90% of cases, reduced the delayed bleeding rate after resection of colorectal polyps measuring 20–50 mm.Trial registration numberUMIN000043675.