《新英格兰医学杂志》英文音频和中文摘要
https://mp.weixin.qq.com/s/gG4Uunu0OCtGb_FDQdk_cA
复发性急性中耳炎鼓膜置管术和药物治疗的比较
背景
关于复发性急性中耳炎患儿的鼓膜置管术，目前官方建议不统一。
方法
我们将6个月内有至少3次急性中耳炎发作，或者12个月内有至少4次发作且其中至少1次在6个月内的6~35月龄患儿随机分组，两组分别接受鼓膜置管术或者包括发作期抗微生物剂治疗在内的药物治疗。主要结局是2年期间每患儿-年的急性中耳炎平均发作次数（发作率）。
结果
在主要意向治疗分析中，在鼓膜置管术组和药物治疗组中，2年期间每患儿-年的急性中耳炎发作率（±SE）分别为1.48±0.08和1.56±0.08（P=0.66）。由于鼓膜置管术组有10%的患儿未接受鼓膜置管术，并且药物治疗组有16%的患儿应其父母要求接受了鼓膜置管术，因此我们进行了符合方案分析，结果显示相应发作率分别为1.47±0.08和1.72±0.11。在主要分析中，次要结局的结果不一。支持鼓膜置管术的结局包括至急性中耳炎首次发作的时间、各种与发作相关的临床结果以及符合特定治疗失败标准的患儿百分比。支持药物治疗的结局为患儿有耳漏的累计天数。未表现出显著差异的结局包括急性中耳炎的发作频率分布、被判定为重度的发作百分比以及呼吸道分离株的抗微生物剂耐药性。与试验相关的不良事件仅限于本试验次要结局包含的状况。
Result
In our main, intention-to-treat analysis, the rate (±SE) of episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P=0.66). Because 10% of the children in the tympanostomy-tube group did not undergo tympanostomy-tube placement and 16% of the children in the medical-management group underwent tympanostomy-tube placement at parental request, we conducted a per-protocol analysis, which gave corresponding episode rates of 1.47±0.08 and 1.72±0.11, respectively. Among secondary outcomes in the main analysis, results were mixed. Favoring tympanostomy-tube placement were the time to a first episode of acute otitis media, various episode-related clinical findings, and the percentage of children meeting specified criteria for treatment failure. Favoring medical management was children’s cumulative number of days with otorrhea. Outcomes that did not show substantial differences included the frequency distribution of episodes of acute otitis media, the percentage of episodes considered to be severe, and antimicrobial resistance among respiratory isolates. Trial-related adverse events were limited to those included among the secondary outcomes of the trial.
结论
在6~35月龄的复发性急性中耳炎患儿中，鼓膜置管术与药物治疗相比未能显著降低2年期间的急性中耳炎发作率。（由美国国立耳聋和其他沟通障碍研究所[National Institute on Deafness and Other Communication Disorders]等资助；在ClinicalTrials.gov注册号为NCT02567825。）
Conclusions
Among children 6 to 35 months of age with recurrent acute otitis media, the rate of episodes of acute otitis media during a 2-year period was not significantly lower with tympanostomy-tube placement than with medical management. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02567825.)
tezepelumab治疗成人和青少年未受控制的重症哮喘
Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma
背景
tezepelumab是可阻断胸腺基质淋巴细胞生成素的人源性单克隆抗体，而淋巴细胞生成素是与哮喘发病机制有关的上皮细胞源性细胞因子。tezepelumab治疗未受控制的重症哮喘的疗效和安全性需要进一步评估。
我们开展了一项3期、多中心、随机、双盲、安慰剂对照试验。患者（12~80岁）被随机分配接受每4周1次tezepelumab（每次210 mg）或安慰剂皮下给药，持续52周。主要终点是52周期间哮喘的年发作率。我们还在基线血嗜酸性粒细胞计数<300个细胞/μL的患者中评估了这一终点。次要终点包括第1秒用力呼气量（FEV1）以及哮喘控制问卷6（Asthma Control Questionnaire-6，ACQ-6；范围，0[无受损]~6[最严重受损]）、哮喘生活质量问卷（Asthma Quality of Life Questionnaire，AQLQ；范围，1[最严重受损]~7[无受损]）和哮喘症状日记（Asthma Symptom Diary，ASD；范围，0[无症状]~4[可能的最严重症状]）评分。
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire–6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).
共计1061例患者接受了随机分组（529例被分配接受tezepelumab，532例被分配接受安慰剂）。在tezepelumab组和安慰剂组中，哮喘的年发作率分别为0.93（95%置信区间[CI]，0.80~1.07）和2.10（95% CI，1.84~2.39）（率比，0.44；95% CI，0.37~0.53；P<0.001）。在血嗜酸性粒细胞计数<300个细胞/μL的患者中，tezepelumab组和安慰剂组的年发作率分别为1.02（95% CI，0.84~1.23）和1.73（95% CI，1.46~2.05）（率比，0.59；95% CI，0.46~0.75；P<0.001）。第52周时，在支气管扩张剂用药前FEV1（0.23 vs. 0.09 L；差异，0.13 L；95% CI，0.08~0.18；P<0.001）以及ACQ-6（-1.55 vs. -1.22；差异，-0.33；95% CI，-0.46~-0.20；P<0.001）、AQLQ（1.49 vs. 1.15；差异，0.34；95% CI，0.20~0.47；P<0.001）和ASD评分（-0.71 vs. -0.59；差异, -0.12；95% CI，-0.19~-0.04；P=0.002）方面，tezepelumab组的改善幅度超过安慰剂组。两组的不良事件发生率和类型不存在有意义的差异。
Result
结论
在未受控制的重症哮喘患者中，接受tezepelumab的患者与接受安慰剂的患者相比，前者的哮喘发作较少，并且肺功能、哮喘控制情况和健康相关生活质量较好。（由阿斯利康和安进资助；NAVIGATOR在ClinicalTrials.gov注册号为NCT03347279。）
Conclusions
Andrew Menzies-Gow, Jonathan Corren, Arnaud Bourdin, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. DOI: 10.1056/NEJMoa2034975
维莫非尼联合利妥昔单抗治疗难治性或复发性毛细胞白血病
Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia
背景
毛细胞白血病（HCL）是CD20+惰性B细胞癌，其中BRAF V600E激酶激活突变起着致病作用。在纳入难治性或复发性HCL患者的临床试验中，应用口服BRAF抑制剂维莫非尼靶向BRAF V600E可使91%的患者达到缓解，使35%的患者达到完全缓解。然而，停药后的中位无复发生存期只有9个月。
结果
在本试验纳入的30例HCL患者中，既往接受过的治疗种数中位数为3种。在意向治疗人群中，本试验观察到26例患者（87%）达到完全缓解。所有化疗（10例）或利妥昔单抗（5例）难治性HCL患者以及所有接受过BRAF抑制剂治疗（7例）的患者均达到完全缓解。血小板减少症在中位2周后消退，中性粒细胞减少症在中位4周后消退。在26例完全缓解的患者中，17例（65%）清除了微小残留病变（MRD）。在中位37个月随访时，全部30例患者的无进展生存率为78%；在中位34个月随访时，26例达到缓解患者的无复发生存率为85%。在事后分析中，MRD阴性和既往未接受过BRAF抑制剂治疗与较长的无复发生存期相关。毒性作用（大多为1级或2级的）均为既往已在这些药物中观察到的毒性作用。
Result
Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents.
结论
在此项小规模研究中，维莫非尼联合利妥昔单抗这一不含化疗药物，且无骨髓毒性的短疗程治疗方案使大多数难治性或复发性HCL患者达到持久完全缓解。（由欧洲研究理事会[European Research Council]等资助；HCL-PG03在EudraCT注册号为2014-003046-27。）
Conclusions
Ad26.COV2.S COVID-19 疫苗1–2a期试验的期中结果
背景
我们亟需有效疫苗来遏制SARS-CoV-2引起的COVID-19疫情。候选疫苗Ad26.COV2.S是一种重组且无复制能力的腺病毒血清型26（Ad26）载体，可编码稳定的全长SARS-CoV-2刺突蛋白。
方法
在此项多中心、安慰剂对照的1-2a期试验中，我们将18~55岁（队列1）和≥65岁（队列3）的健康成人随机分组，分别采用一剂或两剂方案接种Ad26.COV2.S疫苗（剂量为5×1010个病毒颗粒/mL[小剂量]或1×1011个病毒颗粒/mL[大剂量]）或安慰剂。我们正在队列2中收集比较一剂方案和两剂方案的较长期数据；本文未报告这些结果。主要终点是各种接种方案的安全性和反应原性。
In this multicenter, placebo-controlled, phase 1–2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule.
结果
队列1和3的805例参与者接种第1剂疫苗后，以及队列1的参与者接种第2剂疫苗后，最常见的征集的不良事件包括疲劳、头痛、肌痛和注射部位疼痛。最常见的全身性不良事件是发热。队列3的全身性不良事件发生率低于队列1，接种小剂量疫苗后的全身性不良事件发生率低于接种大剂量疫苗后。接种第2剂疫苗后的反应原性较低。不论疫苗剂量或年龄组如何，在接种第1剂疫苗后第29日，我们均在≥90%参与者体内检出抗野生型病毒的中和抗体滴度（几何平均滴度[GMT]，224~354），并且队列1a在截至第57日时达到100%，且滴度进一步升高（GMT，288~488）。滴度保持稳定至至少第71日。第2剂疫苗使滴度升高至之前的2.6~2.9倍（GMT，827~1266）。刺突结合抗体应答与中和抗体应答相似。第15日时，我们在队列1中76%~83%参与者和队列3中60%~67%参与者体内检出CD4+ T细胞应答，明显倾向于1型辅助T细胞。CD8+ T细胞应答总体稳定，但在队列3中较低。
Result
After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354), regardless of vaccine dose or age group, and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3.
结论
Ad26.COV2.S的安全性和免疫原性支持我们进一步开发这一候选疫苗。（由强生公司及美国卫生和人类服务部[Department of Health and Human Services]生物医学和高级研究与开发管理局[Biomedical and Advanced Research and Development Authority]资助；COV1001在ClinicalTrials.gov注册号为NCT04436276。）
Conclusions