NEJM original articles

Background. More evidence is needed to inform recommendations for intervals of colonoscopy surveillance after polyp removal.

Methods. In this ongoing noninferiority trial conducted in eight European countries, we randomly assigned patients with high-risk adenomas (defined as ≥1 adenoma with a diameter of ≥10 mm, high-grade dysplasia, or villous growth or 3 to 10 adenomas of any kind) to undergo a first colonoscopy at 5 years after polyp removal or at 3 years; surveillance at 3 years is currently recommended in guidelines. The 3-year group also underwent colonoscopy at 5 years. The primary end point is the cumulative incidence of colorectal cancer at 10 years, with a prespecified noninferiority margin of 0.7 percentage points for the upper boundary of the confidence interval for the difference between the two groups. Here, we report the results of an interim analysis conducted after 5.5 years of follow-up. Inverse probability weighting was used to account for missing data owing to nonparticipation in surveillance colonoscopy at 5 years. In this analysis, the incidence of colorectal cancer is reported with a one-sided 99.12% confidence interval; for the final analysis at 10 years, the plan is to calculate a 95.33% confidence interval to maintain an overall type I error of 5%.

Results. A total of 10,799 patients underwent randomization: 5398 patients were assigned to the 5-year group and 5401 to the 3-year group. The 5-year cumulative incidence of colorectal cancer was 0.77% with less-frequent surveillance and 0.82% with more-frequent surveillance (difference, -0.05 percentage points); the upper boundary of the 99.12% confidence interval was 0.68, which met the criterion for noninferiority. The distribution of cancer stage at diagnosis did not appear to differ substantially between the two groups. A total of 5 patients died of colorectal cancer: 3 patients (0.06%) in the 5-year group and 2 (0.04%) in the 3-year group.

Conclusions. In this interim analysis of a 10-year noninferiority trial, beginning surveillance colonoscopy at 5 years after polyp removal was noninferior to beginning at 3 years with respect to the cumulative incidence of colorectal cancer at 5 years among patients with high-risk adenomas. (Funded by the Research Council of Norway and others; EPoS II ClinicalTrials.gov number, NCT02319928.).

Background. Metabolic acidosis is common in critically ill patients and is associated with organ dysfunction and death. Sodium bicarbonate is used to correct acidemia, but its benefit in patients with metabolic acidosis who are receiving vasopressors remains uncertain.

Methods. In this pragmatic, adaptive, double-blind, randomized trial, we assigned adults with metabolic acidosis (pH, <7.30; base excess, no more than -4 mmol per liter; and partial pressure of arterial carbon dioxide, ≤45 mm Hg without intubation or ≤50 mm Hg with intubation) who were receiving vasopressors in the intensive care unit (ICU) to receive either sodium bicarbonate or placebo (5% dextrose). Sodium bicarbonate or placebo was infused for up to 5 hours, with the infusion rate adjusted for a target pH of at least 7.30 and base excess of at least 0 mmol per liter. The primary outcome was a major adverse kidney event, defined as death, use of renal-replacement therapy, or persistent renal dysfunction, within 30 days.

Results. A total of 500 patients were enrolled in 55 ICUs across seven countries; 245 patients were assigned to receive sodium bicarbonate and 255 to receive placebo. A major adverse kidney event within 30 days occurred in 98 of 244 patients (40.2%) in the sodium bicarbonate group and in 100 of 254 patients (39.4%) in the placebo group (adjusted difference, 1.2 percentage points; 95% confidence interval [CI], -7.1 to 9.4; P = 0.78). Renal-replacement therapy was used within 30 days in 16.8% of the patients in the sodium bicarbonate group and in 20.9% of those in the placebo group (adjusted difference, -3.9 percentage points; 95% CI, -10.6 to 2.7). In-hospital mortality by day 30 was 25.4% in the sodium bicarbonate group and 24.0% in the placebo group (adjusted difference, 1.8 percentage points; 95% CI, -5.6 to 9.2). Four patients (1.6%) in the sodium bicarbonate group had an adverse effect, as compared with none in the placebo group (P = 0.06).

Conclusions. The use of sodium bicarbonate in critically ill patients with metabolic acidosis receiving vasopressors did not lead to a lower risk of major adverse kidney events within 30 days than placebo. (Funded by the National Health and Medical Research Council of Australia; SODa-BIC ClinicalTrials.gov number, NCT05697770.).

Background. Blinatumomab, a bispecific T-cell engager targeting the CD19 antigen on B cells, may offer an option to safely replace cycles of traditional chemotherapy in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL).

Methods. We randomly assigned, in a 1:1 ratio, children with high-risk B-cell ALL to receive two cycles of blinatumomab (blinatumomab group) or two cycles of chemotherapy (control group) after consolidation. The primary end point was event-free survival as evaluated in a time-to-event analysis; the duration of event-free survival was defined as the time from randomization to the first event among resistance to protocol treatment, relapse, second cancer, or death from any cause. Our primary objective was to evaluate whether the 4-year event-free survival would be 10 percentage points higher in the blinatumomab group than in the control group.

Results. Overall, 709 of 768 eligible patients (92.3%) underwent randomization; 358 were assigned to the blinatumomab group and 351 to the control group. A planned interim analysis at a median follow-up of 2.9 years showed an estimated 4-year event-free survival of 83.0% (95% confidence interval [CI], 77.4 to 87.4) in the blinatumomab group and 70.3% (95% CI, 63.8 to 75.9) in the control group (P = 0.0002 in an intention-to-treat analysis). The estimated hazard ratio for a primary end-point event (blinatumomab vs. control) was 0.51 (95% CI, 0.35 to 0.73) as assessed with a Cox model. Infection related to the trial treatment occurred in 23.9% of patients in the blinatumomab group and in 69.4% of those in the control group (P<0.001). Life-threatening adverse events occurred in 2 patients (0.5%) in the blinatumomab group, including one (in 0.3%) that was fatal, and in 16 patients (4.7%) in the control group. Neurotoxic events were reported in 12.0% and 3.2%, respectively (P<0.001). Cytokine release syndrome of grade 2 or higher occurred in 1.1% of patients in the blinatumomab group.

Conclusions. In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival at 4 years. (Funded by Deutsche Krebshilfe and others; AIEOP-BFM ALL 2017 EudraCT number, 2016-001935-12; EU Clinical Trials number, 2023-509856-32-00; and ClinicalTrials.gov number, NCT03643276.).

Background. Immune responses leading to food allergy may develop early in life, potentially before the introduction of solid foods. Exposures to food allergens in utero and through breast milk have been proposed as a strategy to prevent food allergies in infants, but evidence from randomized trials is lacking.

Methods. In this multisite, randomized trial, pregnant women whose unborn child had at least two biologic family members with medically diagnosed allergic disease were eligible to participate. Participants were assigned in a 1:1 ratio to follow either a diet high in eggs and peanuts that included at least 6 eggs and 60 peanuts per week (high egg-peanut group) or a standard (control) egg and peanut diet that included no more than 3 eggs and 30 peanuts per week (standard-diet group), from before 23 weeks' gestation until 4 months postnatally during lactation. The primary outcome was IgE-mediated egg or peanut allergy in the infant at 1 year of age.

Results. A total of 1070 participants were assigned to the high egg-peanut group, and 1067 were assigned to the standard-diet group. There was no significant difference in the percentage of infants with IgE-mediated egg or peanut allergy between the maternal high egg-peanut group (83 of 1066, 7.8%) and the standard-diet group (89 of 1064, 8.4%) (relative risk, 0.93; 95% confidence interval, 0.69 to 1.26; P = 0.65). Safety measures were similar in the two groups.

Conclusions. The ingestion of high amounts of egg and peanut during pregnancy and lactation did not result in a significantly lower risk of the development of egg or peanut allergy in infants by 1 year of age than ingestion of low amounts of these foods. (Funded by the Australian National Health and Medical Research Council and others; PrEggNut Australian New Zealand Clinical Trial Registry number, ACTRN12618000937213.).