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Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer可切除局部晚期食管腺癌的最佳多模式疗法尚不明确。一个重要的问题是，围手术期化疗是否优于术前放化疗。The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy.在此项3期多中心随机试验中，我们以1:1比例分配可切除食管腺癌患者接受FLOT（氟尿嘧啶、亚叶酸钙、奥沙利铂和多西他赛）围手术期化疗联合手术或术前放化疗（剂量为41.4 Gy的放疗以及卡铂和紫杉醇）联合手术。患者纳入标准包括原发肿瘤临床分期为cT1 cN+、cT2-4a cN+或cT2-4a cN0，其中T表示肿瘤大小和范围（数字较大表示肿瘤较晚期），N表示癌症是（N+）否（N0）扩散到淋巴结，并且没有转移扩散证据。主要终点是总生存期。In this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2–4a cN+, or cT2–4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival.从2016年2月至2020年4月，我们将221例患者分配到FLOT组，将217例患者分配到术前放化疗组。中位随访时间为55个月，FLOT组的3年总生存率为57.4%（95%置信区间[CI]，50.1~64.0），术前放化疗组为50.7%（95% CI，43.5~57.5）（死亡风险比，0.70；95% CI，0.53~0.92；P=0.01）。FLOT组的3年无进展生存率为51.6%（95% CI，44.3~58.4），术前放化疗组为35.0%（95% CI，28.4~41.7）（疾病进展或死亡的风险比，0.66；95% CI，0.51~0.85）。在开始接受所分配治疗的患者中，FLOT组207例患者中的120例（58.0%）和术前放化疗组196例患者中的98例（50.0%）发生了3级或更高级别不良事件。FLOT组207例患者中的98例（47.3%）和术前放化疗组196例患者中的82例（41.8%）发生了严重不良事件。FLOT组的术后90天死亡率为3.1%，术前放化疗组为5.6%。From February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P=0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative-chemoradiotherapy group.与术前放化疗相比，FLOT围手术期化疗可提高可切除食管腺癌患者的生存率。（由德国研究基金会[German Research Foundation]资助；ESOPEC在ClinicalTrials.gov注册号为NCT02509286）。Perioperative chemotherapy with FLOT led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy. (Funded by the German Research Foundation; ESOPEC ClinicalTrials.gov number, NCT02509286.)Jens Hoeppner, Thomas Brunner, Claudia Schmoor, et al. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. DOI: 10.1056/NEJMoa2409408
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院外心脏停搏患者用药途径随机试验
A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest
对于院外心脏停搏患者，肾上腺素等药物的效果与用药时间密切相关。骨内用药途径可能比静脉用药途径更快速，但其对临床结局的影响尚不确定。In patients with out-of-hospital cardiac arrest, the effectiveness of drugs such as epinephrine is highly time-dependent. An intraosseous route of drug administration may enable more rapid drug administration than an intravenous route; however, its effect on clinical outcomes is uncertain.我们在英国11个急救医疗系统开展了一项多中心、开放标签、随机试验，试验参与者为需要通过血管通路用药的心脏停搏成人。患者被随机分成两组，分别由急救人员首先通过骨内或首先通过静脉内血管通路用药。主要结局是30日时存活。关键次要结局包括自主循环恢复以及出院时神经功能良好（定义为改良Rankin量表评分≤3分，该量表评分范围为0~6分，评分较高表示失能较严重）。本试验未进行多重性校正。We conducted a multicenter, open-label, randomized trial across 11 emergency medical systems in the United Kingdom that involved adults in cardiac arrest for whom vascular access for drug administration was needed. Patients were randomly assigned to receive treatment from paramedics by means of an intraosseous-first or intravenous-first vascular access strategy. The primary outcome was survival at 30 days. Key secondary outcomes included any return of spontaneous circulation and favorable neurologic function at hospital discharge (defined by a score of 3 or less on the modified Rankin scale, on which scores range from 0 to 6, with higher scores indicating greater disability). No adjustment for multiplicity was made.共计6082例患者被分组：3040例患者被分配到骨内用药组，3042例患者被分配到静脉内用药组。30日时，骨内用药组3030例患者中的137例（4.5%）和静脉内用药组3034例患者中的155例（5.1%）仍存活（校正后的比值比，0.94；95%置信区间[CI]，0.68~1.32；P=0.74）。出院时，骨内用药组2994例患者中80例（2.7%）和静脉内用药组2986例患者中85例（2.8%）的神经结局良好（校正后的比值比，0.91；95% CI，0.57~1.47）；两组分别有3031例患者中的1092例（36.0%）和3035例患者中的1186例（39.1%）在任何时间恢复自主循环（校正后的比值比，0.86；95% CI，0.76~0.97）。试验期间，骨内用药组发生了一起不良事件。A total of 6082 patients were assigned to a trial group: 3040 to the intraosseous group and 3042 to the intravenous group. At 30 days, 137 of 3030 patients (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group were alive (adjusted odds ratio, 0.94; 95% confidence interval [CI], 0.68 to 1.32; P=0.74). At the time of hospital discharge, a favorable neurologic outcome was observed in 80 of 2994 patients (2.7%) in the intraosseous group and in 85 of 2986 (2.8%) in the intravenous group (adjusted odds ratio, 0.91; 95% CI, 0.57 to 1.47); a return of spontaneous circulation at any time occurred in 1092 of 3031 patients (36.0%) and in 1186 of 3035 patients (39.1%), respectively (adjusted odds ratio, 0.86; 95% CI, 0.76 to 0.97). During the trial, one adverse event, which occurred in the intraosseous group, was reported.在需要药物治疗的院外心脏停搏成人患者中，首先通过骨内血管通路用药与首先通过静脉内血管通路用药相比，并未提高30日生存率。（由英国国家卫生和医疗研究所[National Institute for Health and Care Research]资助；PARAMEDIC-3在ISRCTN注册号为ISRCTN14223494）。Among adults with out-of-hospital cardiac arrest requiring drug therapy, the use of an intraosseous-first vascular access strategy did not result in higher 30-day survival than an intravenous-first strategy. (Funded by the National Institute for Health and Care Research; PARAMEDIC-3 ISRCTN Registry number, ISRCTN14223494.)Keith Couper, Chen Ji, Charles D. Deakin, et al.A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest. DOI:10.1056/NEJMoa2407780
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Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest院外心脏停搏是全球范围内导致死亡的主要原因。在心肺复苏过程中，建立血管通路对于施用指南推荐的药物至关重要。常规使用的是骨内途径和静脉内途径，但这两种途径的效果比较仍不明确。Out-of-hospital cardiac arrest is a leading cause of death worldwide. Establishing vascular access is critical for administering guideline-recommended drugs during cardiopulmonary resuscitation. Both the intraosseous route and the intravenous route are used routinely, but their comparative effectiveness remains unclear.
我们进行了一项随机临床试验，以比较对非创伤性院外心脏停搏成人患者初始尝试骨内或静脉内血管通路的效果。主要结局是持续恢复自主循环。关键次要结局是30日时存活以及30日时存活且神经结局良好，神经结局良好的定义为改良Rankin量表评分为0~3分（评分范围为0~6分，评分较高表示失能较严重）。We conducted a randomized clinical trial to compare the effectiveness of initial attempts at intraosseous or intravenous vascular access in adults who had nontraumatic out-of-hospital cardiac arrest. The primary outcome was a sustained return of spontaneous circulation. Key secondary outcomes were survival at 30 days and survival at 30 days with a favorable neurologic outcome, defined by a score of 0 to 3 on the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability)..在接受随机分组的1506例患者中，有1479例患者被纳入主要分析（骨内通路组731例，静脉内通路组748例）。骨内通路组669例（92%）患者和静脉内通路组595例（80%）患者在最多两次尝试后建立了血管通路。在骨内通路组和静脉内通路组中，分别有221例患者（30%）和214例患者（29%）持续恢复自主循环（危险比，1.06；95%置信区间[CI]，0.90~1.24；P=0.49）。30日时，骨内通路组和静脉内通路组分别有85例（12%）和75例（10%）患者存活（危险比，1.16；95% CI，0.87~1.56）；30日时，两组分别有67例（9%）和59例（8%）患者的神经结局良好（危险比，1.16；95% CI，0.83~1.62）。预设的不良事件并不常见。Among 1506 patients who underwent randomization, 1479 were included in the primary analysis (731 in the intraosseous-access group and 748 in the intravenous-access group). The successful establishment of vascular access within two attempts occurred in 669 patients (92%) assigned to the intraosseous-access group and in 595 patients (80%) assigned to the intravenous-access group. Sustained return of spontaneous circulation occurred in 221 patients (30%) in the intraosseous-access group and in 214 patients (29%) in the intravenous-access group (risk ratio, 1.06; 95% confidence interval [CI], 0.90 to 1.24; P=0.49). At 30 days, 85 patients (12%) in the intraosseous-access group and 75 patients (10%) in the intravenous-access group were alive (risk ratio, 1.16; 95% CI, 0.87 to 1.56); a favorable neurologic outcome at 30 days occurred in 67 patients (9%) and 59 patients (8%), respectively (risk ratio, 1.16; 95% CI, 0.83 to 1.62). Prespecified adverse events were uncommon.在院外心脏停搏成人患者中，初始采用骨内血管通路和静脉内血管通路在持续恢复自主循环方面没有显著差异。（由诺和诺德基金会[Novo Nordisk Foundation]等资助；IVIO在EU临床试验注册系统[EU Clinical Trials Register]注册号为2022-500744-38-00；在ClinicalTrials.gov注册号为NCT05205031）。There was no significant difference in sustained return of spontaneous circulation between initial intraosseous and intravenous vascular access in adults who had out-of-hospital cardiac arrest. (Funded by the Novo Nordisk Foundation and others; IVIO EU Clinical Trials Register number, 2022-500744-38-00; ClinicalTrials.gov number, NCT05205031.)Mikael F. Vallentin, Asger Granfeldt, Thomas L. Klitgaard, et al. Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest. DOI: 10.1056/NEJMoa2407616
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abelacimab与利伐沙班用于心房颤动患者的比较Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillationabelacimab是一种全人源性单克隆抗体，可与非活化形式的因子XI结合并阻止其活化。与口服直接抗凝剂相比，abelacimab对心房颤动患者的安全性尚不清楚。Abelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation. The safety of abelacimab as compared with a direct oral anticoagulant in patients with atrial fibrillation is unknown.将患心房颤动和卒中风险为中危至高危的患者以1:1:1比例随机分组，分别接受盲法皮下注射abelacimab（150 mg或90 mg，每月一次）或开放标签口服利伐沙班（20 mg，每日一次）。主要终点是大出血或临床相关非大出血。Patients with atrial fibrillation and a moderate-to-high risk of stroke were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injection of abelacimab (150 mg or 90 mg once monthly) administered in a blinded fashion or oral rivaroxaban (20 mg once daily) administered in an open-label fashion. The primary end point was major or clinically relevant nonmajor bleeding.共计1287例患者接受了随机分组；患者中位年龄为74岁，44%为女性。3个月时，150 mg abelacimab组的游离因子XI水平中位降幅为99%（四分位距，98~99），90 mg abelacimab组为97%（四分位距，51~99）。根据独立数据监查委员会的建议，本试验提前终止，原因是abelacimab对出血事件的降幅超过预期。150 mg abelacimab组的大出血或临床相关非大出血发生率为3.2起/100人-年，90 mg abelacimab组为2.6起/100人-年，而利伐沙班组为8.4起/100人-年（150 mg abelacimab vs. 利伐沙班的风险比，0.38[95%置信区间{CI}，0.24~0.60]；90 mg abelacimab vs. 利伐沙班的风险比，0.31[95% CI，0.19~0.51]；两项比较的P<0.001）。三组的不良事件发生率和严重程度似乎相似。A total of 1287 patients underwent randomization; the median age was 74 years, and 44% were women. At 3 months, the median reduction in free factor XI levels with abelacimab at a dose of 150 mg was 99% (interquartile range, 98 to 99) and with abelacimab at a dose of 90 mg was 97% (interquartile range, 51 to 99). The trial was stopped early on the recommendation of the independent data monitoring committee because of a greater-than-anticipated reduction in bleeding events with abelacimab. The incidence rate of major or clinically relevant nonmajor bleeding was 3.2 events per 100 person-years with 150-mg abelacimab and 2.6 events per 100 person-years with 90-mg abelacimab, as compared with 8.4 events per 100 person-years with rivaroxaban (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% confidence interval {CI}, 0.24 to 0.60]; hazard ratio for 90-mg abelacimab vs. rivaroxaban, 0.31 [95% CI, 0.19 to 0.51]; P<0.001 for both comparisons). The incidence and severity of adverse events appeared to be similar in the three groups.在患心房颤动且卒中风险为中危至高危的患者中，与利伐沙班治疗相比，abelacimab治疗明显降低了游离因子XI水平，减少了出血事件。（由Anthos Therapeutics资助；AZALEA-TIMI 71在ClinicalTrials.gov注册号为NCT04755283）。Among patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban. (Funded by Anthos Therapeutics; AZALEA–TIMI 71 ClinicalTrials.gov number, NCT04755283.)Christian T. Ruff, Siddharth M. Patel, Robert P. Giugliano, et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. DOI: 10.1056/NEJMoa2406674![]()
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