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2023年2月16日NEJM英文概述00:0029:23 
保乳手术联合或不联合放疗治疗早期乳腺癌的比较 Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer背景 对于接受辅助内分泌治疗的激素受体阳性早期乳腺癌老年女性患者，保乳手术后不进行放疗，目前1级证据有限。 Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor–positive early breast cancer receiving adjuvant endocrine therapy.方法 我们开展了一项省略放疗的3期随机试验；试验人群包括≥65岁激素受体阳性、淋巴结阴性、T1或T2原发乳腺癌（肿瘤最大径≤3 cm）患者，她们接受保乳手术，切缘阴性，并接受辅助内分泌治疗。患者被随机分配接受全乳放疗（40~50 Gy），或者不接受放疗。主要终点是乳腺癌局部复发。本试验还评估了区域复发、乳腺癌特异性生存率、作为首发事件的远处复发和总生存期。 We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor–positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and overall survival were also assessed.结果 共计1326例女性患者被纳入；658例被随机分配接受全乳放疗，668例未接受放疗。中位随访时间为9.1年。在未放疗组和放疗组中，10年内乳腺癌局部复发的累积发生率分别为9.5%（95%置信区间[CI]，6.8~12.3）和0.9%（95% CI，0.1~1.7）（风险比，10.4；95% CI，4.1~26.1；P<0.001）。虽然在未放疗组中局部复发较常见，但未放疗组中作为首发事件的远处复发的10年发生率不比放疗组高，两组发生率分别为1.6%（95% CI，0.4~2.8）和3.0%（95% CI，1.4~4.5）。两组的10年总生存率几乎相同，未放疗组为80.8%（95% CI，77.2~84.3），放疗组为80.7%（95% CI，76.9~84.3）。两组的区域复发率和乳腺癌特异性生存率也无显著差异。 Result A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.
结论 在≥65岁的低风险、激素受体阳性早期乳腺癌女性患者中，省略放疗与局部复发率增加相关，但对作为首发事件的远处复发或总生存期无不利影响。（由苏格兰政府首席科学家办公室[the Chief Scientist Office of the Scottish Government]和爱丁堡西部总医院[Western General Hospital]乳腺癌研究所资助；在ISRCTN注册号为ISRCTN95889329。） Conclusions Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor–positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.)
Ian H. Kunkler, Linda J. Williams, Wilma J.L. Jack, Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. DOI: 10.1056/NEJMoa2207586
NEJM医学前沿 保乳手术后部分乳腺放疗 小程序 老年人接种呼吸道合胞病毒融合前F蛋白疫苗 Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults 背景 呼吸道合胞病毒（RSV）是导致老年人急性呼吸道感染、下呼吸道疾病、临床并发症和死亡的重要原因。目前尚无预防RSV感染的疫苗获批。 Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.在一项正在进行的国际性、安慰剂对照3期试验中，我们以1:1的比例将≥60岁成人随机分组，在RSV感染季前接种单剂以AS01E为佐剂的RSV融合前F蛋白候选疫苗（RSVPreF3 OA）或安慰剂。主要目的是判断在一个RSV感染季内，单剂RSVPreF3 OA疫苗对RSV相关下呼吸道疾病的预防效力；RSV相关疾病通过反转录聚合酶链反应（RT-PCR）证实。主要目的达成的标准是效力估计值置信区间下限大于20%。本试验也评估了疫苗对RSV相关严重下呼吸道疾病和RSV相关急性呼吸道感染的预防效力，并根据RSV亚型（A和B）进行分析。安全性也进行了评估。 In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein–based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. 共计24,966名参与者接受了单剂RSVPreF3 OA疫苗（12,467名参与者）或安慰剂（12,499名）。中位随访6.7个月，疫苗对RT-PCR证实的RSV相关下呼吸道疾病的预防效力为82.6%（96.95% 置信区间[CI]，57.9~94.1），疫苗组和安慰剂组分别有7例（1.0例/1000名参与者-年）和40例（5.8例/1000名参与者-年）参与者发病。疫苗对RSV相关严重下呼吸道疾病（根据临床症状评估或由研究者评估）的预防效力为94.1%（95% CI，62.4~99.9），对RSV相关急性呼吸道感染的预防效力为71.7%（95% CI，56.2~82.3）。疫苗对RSV A和B亚型的预防效力相似（对RSV相关下呼吸道疾病的预防效力分别为84.6%和80.9%；对RSV相关急性呼吸道感染的预防效力分别为71.9%和70.6%）。在不同年龄组和有并发症的参与者中均观察到较高疫苗效力。与安慰剂相比，RSVPreF3 OA疫苗的反应原性更强，而大多数需要报告的不良事件为一过性，严重程度为轻至中度。两组中严重不良事件和潜在免疫介导疾病的发生率相似。 Result A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.结论 在≥60岁成人中，单剂RSVPreF3 OA疫苗具有可接受的安全性，可预防RSV相关急性呼吸道感染、下呼吸道疾病以及RSV相关严重下呼吸道疾病，RSV亚型以及患者有无基础疾病对疫苗效力没有影响。(由葛兰素史克生物公司资助；AReSVi-006在ClinicalTrials.gov注册号为NCT04886596。) Conclusions A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.)Alberto Papi, Michael G. Ison, Joanne M. Langley,Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. DOI: 0.1056/NEJMoa2209604
老年人接种Ad26.RSV.preF–RSV preF蛋白疫苗的效力和安全性 Efficacy and Safety of an Ad26.RSV.preF–RSV preF Protein Vaccine in Older Adults 背景 呼吸道合胞病毒（RSV）可引起老年人严重下呼吸道疾病，但目前尚无获批的RSV疫苗。此前研究显示，编码融合前F（preF）蛋白的腺病毒血清型26（Ad26.RSV.preF）RSV载体与RSV preF蛋白相结合，可诱导体液和细胞免疫反应。 Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity.我们开展了一项随机、双盲、安慰剂对照、2b期概念验证试验，以评估Ad26.RSV.preF–RSV preF蛋白疫苗的效力、免疫原性和安全性。年龄≥65岁成人以1:1的比例随机分配接种疫苗或安慰剂。主要终点是首次发生符合病例3项定义之一的RSV介导的下呼吸道疾病：有≥3种下呼吸道感染症状（定义1），有≥2种下呼吸道感染症状（定义2），以及有≥2种下呼吸道感染症状或≥1种下呼吸道感染症状并且至少1种全身症状（定义3）。We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF–RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3).结果 共计5782名参与者被纳入研究并接受注射。符合病例定义1、2和3的RSV介导的下呼吸道疾病，疫苗接种者分别有6、10和13名，安慰剂接种者分别有30、40和43名。对于病例定义1、2和3，疫苗效力分别为80.0%（94.2%置信区间[CI]，52.2~92.9）、75.0%（94.2% CI，50.1~88.5）和69.8%（94.2% CI，43.7~84.7）。接种疫苗后，RSV A2中和抗体滴度从基线到第15天增加了12.1倍，这一结果与其他免疫原性检测结果一致。疫苗组发生需要报告的局部和全身不良事件的参与者百分比高于安慰剂组（局部，37.9% vs. 8.4%；全身，41.4% vs. 16.4%）；大多数不良事件的严重程度为轻至中度。疫苗组和安慰剂组的严重不良事件发生率相似（分别为4.6%和4.7%）。 Result Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). 结论 在≥65岁成人中，Ad26.RSV.preF–RSV preF蛋白疫苗具有免疫原性，可预防RSV介导的下呼吸道疾病。(由杨森疫苗和预防公司资助；CYPRESS在ClinicalTrials.gov注册号为NCT03982199。) Conclusions In adults 65 years of age or older, Ad26.RSV.preF–RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.)Ann R. Falsey, Kristi Williams, Efi Gymnopoulou,Efficacy and Safety of an Ad26.RSV.preF–RSV preF Protein Vaccine in Older Adults. DOI: 10.1056/NEJMoa2207566
5岁以下儿童接种BNT162b2 Covid-19疫苗评估 Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age 背景 幼童亟需安全有效的2019冠状病毒病（Covid-19）疫苗。 Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children.我们在巴西和加拿大开展了一项随机、对照、适应性平台试验，主要纳入已接种疫苗的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的成人感染者。出现急性COVID-19症状且在症状发生后7日内就诊的门诊患者接受聚乙二醇化干扰素λ（单次皮下注射，180 μg）或安慰剂（单次注射或口服）。主要复合结局是随机分组后28日内因COVID-19住院（或者转诊至三级医院）或到急诊就诊（观察>6小时）。We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.结果 在1期剂量探索试验中，分别有16名6个月至<2岁儿童（3-μg）和48名2至4岁儿童（3-μg或10-μg）接种2剂BNT162b2（间隔21天）。3-μg水平被选择用于2-3期试验；1178名6个月至＜2岁儿童和1835名2至4岁儿童接种BNT162b2，分别有598名和915名儿童接种安慰剂。在两个年龄组中，接种第3剂1个月后的几何平均比率和血清应答的免疫桥接成功标准都达到。BNT162b2的反应原性事件多为轻至中度，未发生4级事件。在接种BNT162b2（6个月至<2岁儿童为7%，2至4岁儿童为5%）和安慰剂（6个月至<2岁儿童为6%~7%，2至4岁儿童为4%~5%）后，两组的发热发生率相似，均较低。在6个月至4岁儿童中，从第3剂疫苗接种后7天开始（基于34例患者），疫苗对有症状Covid-19的总体预防效力是73.2%（95%置信区间，43.8~87.6）。 Result During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-μg dose) and 48 children 2 to 4 years of age (3-μg or 10-μg dose). The 3-μg dose level was selected for the phase 2–3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases).在6个月至4岁儿童中，接种3剂3-μg BNT162b2疫苗安全，具有免疫原性，而且可有效预防Covid-19。(由BioNTech和辉瑞公司资助；ClinicalTrials.gov注册号为NCT04816643）。Conclusions A three-dose primary series of 3-μg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.)Ann R. Falsey, Kristi Williams, Efi Gymnopoulou,Efficacy and Safety of an Ad26.RSV.preF–RSV preF Protein Vaccine in Older Adults. DOI: 10.1056/NEJMoa2207566
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