原创 李向东 华西医院耳鼻喉科

华西耳鼻喉前沿学术速递——文献导读（第55期）

【The New England Journal of Medicine】

2024年9-10月文献导读

期刊介绍：

《新英格兰医学杂志》（The New England Journal of Medicine，简称NEJM），是由美国麻州医学协会（Massachusetts Medical Society）所出版的评审性质医学期刊（medical journal）和综合性医学期刊，创刊于1812年，创始人为美国波士顿著名外科医生约翰·科林斯·瓦伦和麻省总医院创始人詹姆斯·杰克逊，始称《新英格兰医学与外科杂志》。《新英格兰医学杂志》是全球影响因子最高的医学学术期刊，影响因子大概为70。

本期新英格兰共发表论著31篇。

1.Doxorubicin–Trabectedin with Trabectedin Maintenance in Leiomyosarcoma

多柔比星-曲贝替定联合治疗与曲贝替定维持治疗在平滑肌肉瘤中的作用

法国居斯塔夫-鲁西研究所

Abstract

Background：The addition of trabectedin to doxorubicin, followed by trabectedin maintenance, may have superior efficacy to doxorubicin alone as first-line treatment in patients with advanced leiomyosarcoma.

Methods：We conducted a phase 3 trial involving patients with metastatic or unresectable leiomyosarcoma who had not received chemotherapy previously. Patients were randomly assigned to receive either single-agent doxorubicin (six cycles) or doxorubicin plus trabectedin (six cycles), with continued trabectedin as maintenance therapy in patients in the doxorubicin–trabectedin group who did not have disease progression. Surgery to resect residual disease was allowed in each group after six cycles of therapy. Analyses of progression-free survival (primary end point) and overall survival (secondary end point) were adjusted for two stratification factors: tumor origin site (uterine vs. soft tissue) and disease stage (locally advanced vs. metastatic). The primary end-point results were reported previously.

Results：A total of 150 patients underwent randomization. At a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients had died (47 in the doxorubicin–trabectedin group and 60 in the doxorubicin group). The median overall survival was longer in the doxorubicin–trabectedin group (33 months; 95% confidence interval [CI], 26 to 48) than in the doxorubicin group (24 months; 95% CI, 19 to 31); the adjusted hazard ratio for death was 0.65 (95% CI, 0.44 to 0.95). In a finding consistent with earlier reports, progression-free survival was longer in the doxorubicin–trabectedin group (12 months; 95% CI, 10 to 16) than in the doxorubicin group (6 months; 95% CI, 4 to 7); the adjusted hazard ratio for progression or death was 0.37 (95% CI, 0.26 to 0.53). The incidence of adverse events and the percentage of patients with dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone.

Conclusions：Combination therapy with doxorubicin and trabectedin induction, followed by trabectedin maintenance, was associated with improved overall survival and progression-free survival, as compared with doxorubicin alone, among patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma.

背景：对于晚期平滑肌肉瘤患者，在多柔比星基础上加用曲贝替定，随后维持曲贝替定，作为一线治疗可能比单用多柔比星有效。

方法：研究者进行了一项III期临床试验，招募了未接受过化疗的转移性或不可切除的平滑肌肉瘤患者。患者被随机分配接受单药多柔比星（6个周期）或联合曲贝替定（6个周期），联合组中没有疾病进展的患者继续曲贝替定作为维持治疗。治疗6个周期后，各组均允许手术切除残留病变。无进展生存期（主要终点）和总生存期（次要终点）的分析根据两个分层因素进行调整：肿瘤起源部位（子宫与软组织）和疾病分期（局部晚期与转移性）

结果：共150例患者接受随机化。中位随访时间为55个月，共有107例患者死亡（多柔比星-曲贝替定组47例，多柔比星组60例）。多柔比星-曲贝替定组的中位总生存期（33个月）长于多柔比星组（24个月）。

结论：在转移性或手术不可切除的子宫或软组织平滑肌肉瘤患者中，与单用多柔比星相比，多柔比星和曲贝替定诱导联合治疗，随后维持曲贝替定，与总生存期和无进展生存期改善相关。

2.A Monoclonal Antibody to PACAP for Migraine Prevention

抗PACAP单克隆抗体预防偏头痛的研究

哥本哈根大学医院-丹麦头痛中心神经科

Abstract

Background：Targeting pituitary adenylate cyclase–activating polypeptide (PACAP) is a new avenue for treating migraine. The efficacy and safety of intravenous Lu AG09222, a humanized monoclonal antibody directed against the PACAP ligand, for migraine prevention are unclear.

Methods：In a phase 2, double-blind, randomized, placebo-controlled trial, we enrolled adult participants (18 to 65 years of age) with migraine for whom two to four previous preventive treatments had failed to provide a benefit. The trial included a 4-week treatment period and an 8-week follow-up period. Participants were randomly assigned in a 2:1:2 ratio to receive a single-dose baseline infusion of 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo. The primary end point was the mean change from baseline in the number of migraine days per month, during weeks 1 through 4, in the Lu AG09222 750-mg group as compared with the placebo group.

Results：Of 237 participants enrolled, 97 received 750 mg of Lu AG09222, 46 received 100 mg of Lu AG09222, and 94 received placebo. The mean number of baseline migraine days per month was 16.7 in the overall population, and the mean change from baseline over weeks 1 through 4 was −6.2 days in the Lu AG09222 750-mg group, as compared with −4.2 days in the placebo group (difference, −2.0 days; 95% confidence interval, −3.8 to −0.3; P=0.02). Adverse events with a higher incidence in the Lu AG09222 750-mg group than in the placebo group during the 12-week observation period included coronavirus disease 2019 (7% vs. 3%), nasopharyngitis (7% vs. 4%), and fatigue (5% vs. 1%).

Conclusions：In a phase 2 trial, a single intravenous infusion of 750 mg of Lu AG09222 showed superiority over placebo in reducing migraine frequency over the subsequent 4 weeks. 

背景：靶向垂体腺苷酸环化酶激活多肽（PACAP）是治疗偏头痛的新途径。静脉注射Lu AG09222（一种针对PACAP配体的人源化单克隆抗体）预防偏头痛的有效性和安全性尚不清楚。

方法：一项2期、双盲、随机、安慰剂对照试验中，招募了患有偏头痛的成年参与者（18至65岁），他们之前的2至4次预防性治疗未能提供益处。试验包括4周的治疗期和8周的随访期。参与者以2：1：2的比例随机分配接受750 mg Lu AG09222，100 mg Lu AG09222和安慰剂的单剂量基线输注。主要终点是Lu AG 09222 750 mg组与安慰剂组相比，第1周至第4周期间每月偏头痛天数较基线的平均变化。

结果：在237名参与者中，97人接受了750 mg Lu AG 09222，46人接受了100 mg Lu AG 09222，94人接受了安慰剂。总体人群中每月平均基线偏头痛天数为16.7天，Lu AG 09222 750 mg组第1周至第4周较基线的平均变化为-6.2天，而安慰剂组为-4.2天（差异为-2.0天）。在12周观察期内，Lu AG 09222 750 mg组发生率高于安慰剂组的不良事件包括2019冠状病毒病（7% vs. 3%）、鼻咽炎（7% vs. 4%）和疲乏（5% vs. 1%）。

结论：单次静脉输注750 mg Lu AG 09222在随后4周内降低偏头痛频率方面优于安慰剂。

3.Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke

阿加曲班或依替巴肽联合静脉注射治疗缺血性脑卒中

圣路易斯华盛顿大学急诊医学-神经病学-康复医学系

Abstract

Background：Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear.

Methods：We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization.

Results：A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, −1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, −0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%).

Conclusions：In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality.

背景：静脉溶栓是急性缺血性中风的标准治疗方法。静脉溶栓联合阿加曲班（一种抗凝剂）或依替巴肽（一种抗血小板剂）的疗效和安全性尚不清楚。

方法：在美国的57个地点进行了一项3期、三组、适应性、单盲、随机、对照临床试验。纳入的急性缺血性卒中患者在症状出现后3小时内接受了静脉溶栓治疗，并在溶栓开始后的75分钟内随机分配接受静脉注射阿伽曲班、依普非巴肽或安慰剂治疗。通过集中审查的方式评估主要疗效结局，即效用加权90天改良兰金量表评分（范围为0至10，评分越高反映结局越好）。主要安全性结局为随机化后36小时内的症状性颅内出血。

结果：共有514例患者被分配接受阿加曲班（59例患者），依替巴肽（227例患者）或安慰剂（228例患者）。所有患者均接受静脉溶栓（70%接受阿替普酶，30%接受替奈普酶），225例患者（44%）接受血管内血栓切除术。在90天时，阿加曲班组、依替巴肽组和安慰剂组的平均（±SD）效用加权改良兰金量表评分分别为5.2±3.7、6.3±3.2和6.8±3.0。阿加曲班优于安慰剂的后验概率为0.002（效用加权改良兰金量表评分的后验平均差异为−1.51±0.51），依替巴肽优于安慰剂的后验概率为0.041（后验平均差异为−0.50±0.29）。三组症状性颅内出血的发生率相似（阿加曲班组为4%，依替巴肽组为3%，安慰剂组为2%）。阿加曲班组（24%）和依替巴肽组（12%）的90天死亡率高于安慰剂组（8%）。

结论：在症状发作后3小时内接受静脉溶栓治疗的急性缺血性卒中患者中，静脉注射阿加曲班或依替巴肽的连续治疗不能减少卒中后残疾，并与死亡率增加相关。

4.A New Orthonairovirus Associated with Human Febrile Illness

一种新的与人类发热性疾病相关的正鼻病毒

北京微生物与流行病学研究所病原与生物安全国家重点实验室

Abstract

Background：In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV).

Methods：We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models.

Results：WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase–polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV.

Conclusions：A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. 

背景：2019年6月，一名患者在内蒙古某湿地公园被蜱虫叮咬后出现持续发热和多器官功能障碍。该患者的下一代测序显示感染了一种以前未知的正鼻病毒，研究者将其命名为湿地病毒（Wetland virus，WELV）。

方法：进行了积极的医院为基础的监测，以确定在有蜱叮咬史的发热患者中WELV感染的患病率。分离病毒，并在动物模型中研究其感染性和致病性。

结果：WELV是奈罗病毒科中正空病毒属的一员，与蜱传哈扎拉正空病毒基因组关系最密切。采用逆转录聚合酶链反应（RT-PCR）方法，对内蒙古、黑龙江、吉林、辽宁等地17例患者进行了急性WELV感染的检测。这些患者表现为非特异性症状，包括发热、头晕、头痛、不适、肌痛、关节炎和背痛，较少出现瘀点和局部淋巴结病。1例患者出现神经系统症状。常见的实验室检查结果为白细胞减少、血小板减少、D-二聚体和乳酸脱氢酶水平升高。对8例患者的恢复期样本进行血清学评估，结果显示，WELV特异性抗体滴度是急性期样本的4倍。 在中国东北地区采集的5种蜱类和绵羊、马、猪、高原鼢鼠（Myospalax psilurus）体内均检测到WELV RNA。从指示患者和蜱中分离的病毒在人脐静脉内皮细胞中显示出细胞病变效应。BALB/c、C57 BL/6和昆明种小鼠腹腔注射病毒可导致致死性感染。血蜱是一种可能的媒介，可以经卵巢传播WELV。

结论：在中国东北地区发现了一种与人类发热性疾病相关的新发现的正鼻病毒。

5.Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

阿希替尼在新诊断慢性粒细胞白血病中的应用

德国耶拿大学医院第二内科诊所

Abstract

Background：Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).

Methods：In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.

Results：A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).

Conclusions：In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. 

背景：新诊断的慢性粒细胞白血病（CML）患者需要长期有效和安全的治疗。Asciminib是一种BCR：：ABL 1抑制剂，特异性靶向ABL肉豆蔻酰口袋，可能比目前可用的一线ATP竞争性酪氨酸激酶抑制剂（TKI）提供更好的疗效和安全性，副作用更少。

方法：一项III期试验中，新诊断的CML患者以1：1的比例随机分配接受阿昔替尼（80 mg，每日一次）或一种药物选择的TKI，随机化按欧洲治疗和结局研究长期生存评分类别（低、中或高风险）和随机化前研究者选择的TKI（包括伊马替尼和第二代TKI）分层。主要终点为第48周时的主要分子学缓解（定义为国际量表[IS]上的BCR：：ABL1转录水平≤0.1%），在预随机化选择的伊马替尼分层中比较阿希替尼与研究者选择的TKIs，以及阿希替尼与研究者选择的酪氨酸激酶抑制剂之间的差异。

结果：共有201例患者被分配接受阿希替尼治疗，204例患者被分配接受经药物选择的TKI治疗。阿希替尼组的中位随访时间为16.3个月，替吉奥选择的TKI组为15.7个月。第48周时，阿希替尼组67.7%的患者出现主要分子学缓解，而选择性治疗组为49.0%，在伊马替尼分层中，阿希替尼组69.3%的患者与伊马替尼组40.2%的患者。在第二代TKI分层中，第48周时发生主要分子学缓解的患者百分比为66.0%（阿希替尼组）和57.8%（TKI组）。阿西替尼组3级或以上不良事件和导致试验方案终止的事件发生率（分别为38.0%和4.5%）低于伊马替尼组（44.4%和11.1%）和第二代TKI组（54.9%和9.8%）。

结论：在新诊断的慢性期CML患者中，阿昔替尼显示出更好疗效和良好的安全性特征。

6.Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed HyperlipidemiaPlozasiran

一种靶向APOC 3的RNA干扰剂，用于混合型高血压

美国德克萨斯州休斯顿市贝勒医学院

Abstract

Background：Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non–high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)–mediated inhibition of lipoprotein lipase.

Methods：We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24.

Results：A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of −49.8 percentage points (95% confidence interval [CI], −59.0 to −40.6) with the 10-mg-quarterly dose, −56.0 percentage points (95% CI, −65.1 to −46.8) with the 25-mg-quarterly dose, −62.4 percentage points (95% CI, −71.5 to −53.2) with the 50-mg-quarterly dose, and −44.2 percentage points (95% CI, −53.4 to −35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.

Conclusions：In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted.

背景：混合型高脂血症患者由于非高密度脂蛋白（HDL）胆固醇水平升高而有患动脉粥样硬化性心血管疾病的风险，这是由富含甘油三酯的脂蛋白中的残余胆固醇引起的。通过载脂蛋白C3（APOC 3）介导的脂蛋白脂肪酶抑制作用，甘油三酯脂蛋白的代谢和清除率下调。

方法：一项为期48周、2b期、双盲、随机、安慰剂对照试验，评估了plozasiran（一种肝细胞靶向APOC 3小干扰RNA）在混合性高脂血症患者（即，甘油三酯水平为150 - 499 mg/dl，低密度脂蛋白[LDL]胆固醇水平≥70 mg/dl或非HDL胆固醇水平≥100 mg/dl）。参与者以3：1的比例被分配到四个队列中的每个队列中接受plozasiran或安慰剂。在前三个队列中，参与者在第1天和第12周（每季度一次）接受皮下注射plozasiran（10 mg、25 mg或50 mg）或安慰剂。在第四个队列中，参与者在第1天和第24周（半年剂量）接受50 mg plozasiran或安慰剂。汇总了接受安慰剂的参与者的数据。主要终点是第24周空腹甘油三酯水平的百分比变化。

结果：共有353名参与者接受了随机化。第24周时，观察到plozasiran组空腹甘油三酯水平显著降低，与安慰剂组相比，各剂量组的基线至最小二乘均值百分比变化差异如下：10毫克季度剂量组为−49.8个百分点（95%置信区间[CI]，−59.0至−40.6），25毫克季度剂量组为−56.0个百分点（95% CI，−65.1至−46.8），50毫克季度剂量组为−62.4个百分点（95% CI，−71.5至−53.2），50毫克半年剂量组为−44.2个百分点（95% CI，−53.4至−35.0）（所有比较P<0.001））。在接受安慰剂的参与者中，10%的人观察到血糖控制恶化，在接受10 mg季度剂量的参与者中，12%的人观察到血糖控制恶化，在接受25 mg季度剂量的参与者中，7%的人观察到血糖控制恶化，在接受50 mg季度剂量的参与者中，20%的人观察到血糖控制恶化，在接受50 mg半年剂量的参与者中，21%的人观察到血糖控制恶化。

结论：与安慰剂相比，plozasiran在24周时显著降低了甘油三酯水平

7.Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia

Zodasiran佐达西兰，一种靶向ANGPTL 3的RNAi治疗剂，用于混合性高血压

西奈山福斯特心脏医院

Abstract

Background：Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.

Methods：We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.

Results：A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, −29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively; and for LDL cholesterol level, −16 percentage points, −14 percentage points, and −20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.

Conclusions：In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. 

背景：血管生成素样蛋白3（ANGPTL 3）抑制脂蛋白和内皮脂肪酶以及肝脏对富含甘油三酯的脂蛋白残余物的摄取。ANGPTL 3功能缺失携带者的甘油三酯、低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇和非HDL胆固醇水平较低，动脉粥样硬化性心血管疾病的风险较低。Zodasiran是一种靶向肝脏中ANGPTL 3表达的RNA干扰（RNAi）疗法。

方法：一项双盲、安慰剂对照、剂量范围探索的IIb期试验，以评价佐达西兰在混合性高脂血症（空腹甘油三酯水平为150 - 499 mg/dL，LDL胆固醇水平≥70 mg/dL或非HDL胆固醇水平≥100 mg/dL）成人中的安全性和疗效。合格患者以3：1的比例随机分配，在第1天和第12周接受皮下注射佐达西兰（50、100或200 mg）或安慰剂，并随访至第36周。主要终点是甘油三酯水平从基线到第24周的百分比变化。

结果：共有204例患者接受了随机化。第24周时，在佐达西兰组中观察到ANGPTL 3水平较基线显著平均剂量依赖性降低（与安慰剂相比变化差异，50 mg组为−54个百分点，100 mg组为−70个百分点，200 mg组为−74个百分点），观察到甘油三酯水平显著剂量依赖性降低（与安慰剂相比，变化差异分别为-51个百分点、-57个百分点和-63个百分点）（所有比较P<0.001）。与安慰剂相比，其他较基线变化的差异包括：对于非HDL胆固醇水平，50 mg组为−29个百分点，100 mg组为− 29个百分点，200 mg组为−36个百分点;对于载脂蛋白B水平，分别为−19个百分点、−15个百分点和−22个百分点; LDL胆固醇水平分别为-16个百分点、-14个百分点和-20个百分点。 我们在接受最高剂量佐达西兰的既存糖尿病患者中观察到糖化血红蛋白水平一过性升高。

结论：在混合性高脂血症患者中，佐达西兰与24周时甘油三酯水平显著降低相关。

8.Long-Term Oxygen Therapy for 24 or 15 Hours per Day in Severe Hypoxemia

严重低氧血症患者每天24或15小时长期氧疗

英国伦敦布莱金医院医学部

Abstract

Background：Long-term oxygen supplementation for at least 15 hours per day prolongs survival among patients with severe hypoxemia. On the basis of a nonrandomized comparison, long-term oxygen therapy has been recommended to be used for 24 hours per day, a more burdensome regimen.

Methods：To test the hypothesis that long-term oxygen therapy used for 24 hours per day does not result in a lower risk of hospitalization or death at 1 year than therapy for 15 hours per day, we conducted a multicenter, registry-based, randomized, controlled trial involving patients who were starting oxygen therapy for chronic, severe hypoxemia at rest. The patients were randomly assigned to receive long-term oxygen therapy for 24 or 15 hours per day. The primary outcome, assessed in a time-to-event analysis, was a composite of hospitalization or death from any cause within 1 year. Secondary outcomes included the individual components of the primary outcome assessed at 3 and 12 months.

Results：Between May 18, 2018, and April 4, 2022, a total of 241 patients were randomly assigned to receive long-term oxygen therapy for 24 hours per day (117 patients) or 15 hours per day (124 patients). No patient was lost to follow-up. At 12 months, the median patient-reported daily duration of oxygen therapy was 24.0 hours (interquartile range, 21.0 to 24.0) in the 24-hour group and 15.0 hours (interquartile range, 15.0 to 16.0) in the 15-hour group. The risk of hospitalization or death within 1 year in the 24-hour group was not lower than that in the 15-hour group (mean rate, 124.7 and 124.5 events per 100 person-years, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.72 to 1.36; 90% CI, 0.76 to 1.29; P=0.007 for nonsuperiority). The groups did not differ substantially in the incidence of hospitalization for any cause, death from any cause, or adverse events.

Conclusions：Among patients with severe hypoxemia, long-term oxygen therapy used for 24 hours per day did not result in a lower risk of hospitalization or death within 1 year than therapy for 15 hours per day.

背景：严重低氧血症患者每天至少15小时的长期吸氧可提高生存率。根据非随机比较，长期氧疗被推荐为每天24小时，这是一种负担更重的治疗方案。

方法：为了检验长期氧疗每日24小时与每日15小时的治疗在1年内是否会导致住院或死亡风险较低的假设，进行了一项多中心、基于注册的、随机对照试验，涉及在休息时开始氧疗治疗慢性重度低氧血症的患者。患者被随机分配接受每天24或15小时的长期氧气治疗。在至事件发生时间分析中评估的主要结局是1年内住院或全因死亡的复合终点。次要结局包括在3个月和12个月时评估的主要结局的各个组成部分。

结果：在2018年5月18日至2022年4月4日期间，共有241名患者被随机分配接受每天24小时（117名患者）或每天15小时（124名患者）的长期氧疗。无患者失访。12个月时，24小时组患者报告的每日氧疗中位持续时间为24.0小时（四分位距，21.0 - 24.0），15小时组为15.0小时（四分位距，15.0 - 16.0）。24小时组1年内住院或死亡的风险不低于15小时组（平均发生率分别为124.7和124.5起事件/100人-年;风险比为0.99）。两组在因任何原因住院、因任何原因死亡或不良事件的发生率方面没有实质性差异。

结论：在严重低氧血症患者中，每天24小时的长期氧疗并没有导致1年内住院或死亡的风险低于每天15小时的治疗。

9.Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths

减少阿片类药物过量死亡的社区随机试验

波士顿医疗中心

Abstract

Background：Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices.

Methods：In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults.

Results：During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P=0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year.

Conclusions：In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic.

背景：减少阿片类药物相关过量死亡的循证实践包括对过量的教育，纳洛酮分配，使用药物治疗阿片类药物使用障碍和处方阿片类药物安全性管理。需要更多关于社区参与的干预措施的有效性的数据，以通过加强对这些做法的采用来减少与阿片相关的过量死亡。

方法：这项社区水平的随机分组试验中，随机分配了肯塔基州、马萨诸塞州、纽约和俄亥俄州的67个社区，接受干预（34个社区）或等待名单对照（33个社区），根据州进行分层。该试验是在2019年冠状病毒病（Covid-19）大流行和全国芬太尼相关过量死亡人数激增的背景下进行的。根据城市或农村分类、既往用药过量率和社区人口，试验组在各州内保持平衡。主要结果是社区成年人中阿片类药物相关过量死亡的人数。

结果：在2021年7月至2022年6月的比较期间，干预组和对照组中阿片类药物相关过量死亡的人口平均比率相似（每100 000人死亡47.2人对每100 000人死亡51.7人），调整后的比率为0.91（95%置信区间，0.76 - 1.09; P=0.30）。干预措施对阿片类药物相关过量死亡率的影响在州、城市或农村类别、年龄、性别或种族或族裔群体之间没有明显差异。干预社区从社区选择的806项策略中实施了615项循证实践策略（254项涉及对过量的教育和纳洛酮分配，256项涉及阿片类药物使用障碍的药物使用，105项涉及处方阿片类药物安全性）。在这些循证实践战略中，只有235个（38%）在比较年开始时启动。

结论：在这项为期12个月的多模式干预试验中，社区联盟参与部署循证实践以减少阿片类药物过量死亡，在新冠肺炎大流行和芬太尼相关过量流行的背景下，干预组和对照组的死亡率相似。

10.Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease

Axatilimab治疗复发性或难治性慢性移植物抗宿主病

雷根斯堡大学医院第三医学部

Abstract

Background：Colony-stimulating factor 1 receptor (CSF1R)–dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.

Methods：In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.

Results：A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.

Conclusions：Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. 

背景：集落刺激因子1受体（CSF 1 R）依赖性单核细胞和巨噬细胞是慢性移植物抗宿主病（GVHD）的关键介质，GVHD是异基因造血干细胞移植的主要长期并发症。CSF 1 R阻断抗体axatilimab在慢性GVHD中显示出有希望的临床活性。

方法：这项II期、多国、关键、随机研究中，在复发性或难治性慢性GVHD患者中评价了三种不同剂量的axatilimab。患者被随机分配接受axatilimab静脉给药，剂量为每千克体重0.3 mg，每2周一次（0.3 mg剂量组），剂量为每千克体重1 mg，每2周一次（1 mg剂量组），或剂量为每千克体重3 mg，每4周一次（3 mg剂量组）。主要终点是前6个周期的总体缓解（完全或部分缓解）;关键次要终点是患者报告的慢性GVHD症状负担减轻，通过改良Lee症状量表（范围0 - 100，评分越高表示症状越严重）降低5分以上进行评估。如果95%置信区间的下限超过30%，则满足主要终点。

结果：共入组241例患者（0.3 mg剂量组80例患者，1 mg剂量组81例患者，3 mg剂量组80例患者）。所有组均达到主要终点;在0.3 mg剂量组74%的患者、1 mg剂量组67%的患者和3 mg剂量组50%的患者中观察到总体缓解。三个剂量组中分别有60%、69%和41%的患者报告改良Lee症状量表评分降低5分以上。最常见的不良事件是与CSF 1 R阻断相关的剂量依赖性一过性实验室异常。在0.3 mg剂量组中，6%的患者发生了导致停用axatilimab的不良事件，1 mg剂量组为22%，3 mg剂量组为18%。

结论：靶向CSF1R依赖性单核细胞和巨噬细胞的药物axatilimab在复发性或难治性慢性移植物抗宿主病（GVHD）患者中显示出较高的应答率。

11.Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia

泊马度胺治疗遗传性出血性毛细血管扩张症鼻出血

克利夫兰诊所陶西格癌症中心

Abstract

Background：Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life.

Methods：We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations).

Results：The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was −0.94 points (95% confidence interval [CI], −1.57 to −0.31; P=0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was −1.4 points (95% CI, −2.6 to −0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash.

Conclusions：Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified.

背景：遗传性出血性毛细血管扩张症（HHT）的特征是广泛的毛细血管扩张和动静脉畸形。主要临床表现为鼻出血，导致缺铁性贫血和与健康相关的生活质量下降。

方法：一项随机、安慰剂对照试验，以评估泊马度胺治疗HHT的安全性和有效性。研究者将患者以2：1的比例随机分配，接受泊马度胺4 mg/d或安慰剂治疗24周。主要结局是鼻出血严重程度评分（HHT中经验证的出血评分;范围为0 - 10，评分越高表示出血越严重）从基线至第24周的变化。降低0.71分或以上被认为具有临床意义。一个关键的次要结局是HHT特异性生活质量评分（范围为0 - 16，评分越高表明限制越多）。

结果：在计划的中期分析达到预先设定的疗效阈值后，该试验于2023年6月停止招募。共有144例患者接受随机分组; 95例患者被分配接受泊马度胺治疗，49例患者接受安慰剂治疗。基线平均（±SD）鼻出血严重程度评分为5.0±1.5，结果与中度至重度鼻出血一致。第24周时，泊马度胺组和安慰剂组鼻出血严重程度评分较基线变化的平均差异为-0.94分。两组之间HHT特异性生活质量评分变化的平均差异为-1.4分。泊马度胺组比安慰剂组更常见的不良事件包括中性粒细胞减少症、便秘和皮疹。

结论：在HHT患者中，泊马度胺治疗导致鼻出血严重程度显著、临床相关降低。未发现非预期安全性信号。

12.Results after Four Years of Screening for Prostate Cancer with PSA and MRI

PSA和MRI筛查前列腺癌4年后的结果

萨尔格伦斯卡大学医院泌尿科

Abstract

Background：Data on the efficacy and safety of screening for prostate cancer with magnetic resonance imaging (MRI) are needed from studies of follow-up screening.

Methods：In a population-based trial that started in 2015, we invited men who were 50 to 60 years of age to undergo prostate-specific antigen (PSA) screening. Men with a PSA level of 3 ng per milliliter or higher underwent MRI of the prostate. Men were randomly assigned to the systematic biopsy group, in which they underwent systematic biopsy and, if suspicious lesions were found on MRI, targeted biopsy, or the MRI-targeted biopsy group, in which they underwent MRI-targeted biopsy only. At each visit, men were invited for repeat screening 2, 4, or 8 years later, depending on the PSA level. The primary outcome was detection of clinically insignificant (International Society of Urological Pathology [ISUP] grade 1) prostate cancer; detection of clinically significant (ISUP grade ≥2) cancer was a secondary outcome, and detection of clinically advanced or high-risk (metastatic or ISUP grade 4 or 5) cancer was also assessed.

Results：After a median follow-up of 3.9 years (approximately 26,000 person-years in each group), prostate cancer had been detected in 185 of the 6575 men (2.8%) in the MRI-targeted biopsy group and 298 of the 6578 men (4.5%) in the systematic biopsy group. The relative risk of detecting clinically insignificant cancer in the MRI-targeted biopsy group as compared with the systematic biopsy group was 0.43 (95% confidence interval [CI], 0.32 to 0.57; P<0.001) and was lower at repeat rounds of screening than in the first round (relative risk, 0.25 vs. 0.49); the relative risk of a diagnosis of clinically significant prostate cancer was 0.84 (95% CI, 0.66 to 1.07). The number of advanced or high-risk cancers detected (by screening or as interval cancer) was 15 in the MRI-targeted biopsy group and 23 in the systematic biopsy group (relative risk, 0.65; 95% CI, 0.34 to 1.24). Five severe adverse events occurred (three in the systematic biopsy group and two in the MRI-targeted biopsy group).

Conclusions：In this trial, omitting biopsy in patients with negative MRI results eliminated more than half of diagnoses of clinically insignificant prostate cancer, and the associated risk of having incurable cancer diagnosed at screening or as interval cancer was very low. 

背景：需要从随访筛查研究中获得关于磁共振成像（MRI）筛查前列腺癌的有效性和安全性的数据。

方法：2015年开始的一项基于人群的试验中，邀请50至60岁的男性接受前列腺特异性抗原（PSA）筛查。PSA水平为3 ng/ml或更高的男性接受前列腺MRI检查。男性被随机分配到系统活检组，他们接受系统活检，如果在MRI上发现可疑病变，则进行靶向活检，或MRI靶向活检，他们只接受MRI靶向活检。在每次访问中，男性被邀请在2年，4年或8年后进行重复筛查，这取决于PSA水平。主要结局是检测到临床不显著（国际泌尿病理学会[ISUP] 1级）前列腺癌;检测到临床显著（ISUP ≥2级）癌症是次要结局，还评估了临床晚期或高风险（转移性或ISUP 4级或5级）癌症的检测。

结果：中位随访3.9年（每组约26，000人-年）后，MRI靶向活检组6575例男性中有185例（2.8%）和系统活检组6578例男性中有298例（4.5%）检出前列腺癌。与系统活检组相比，MRI靶向活检组检出临床上无意义癌症的相对风险为0.43，重复筛选时低于第一轮（相对风险，0.25 vs. 0.49）;诊断为临床显著前列腺癌的相对风险为0.84。在MRI靶向活检组中检测到的晚期或高危癌症（通过筛查或作为间隔期癌症）的数量为15例，在系统性活检组中为23例。发生了5起严重不良事件（系统性活检组3起，MRI靶向活检组2起）。

结论：在这项试验中，省略对MRI结果为阴性的患者进行活检，消除了一半以上临床上不显著的前列腺癌诊断，并且在筛选时诊断为不可治愈的癌症或作为间隔癌症的相关风险非常低。

13.Ziresovir in Hospitalized Infants with Respiratory Syncytial Virus Infection

齐瑞索韦治疗呼吸道合胞病毒感染住院婴儿

上海方舟生物制药有限公司、华西二院、北京儿童医院

Abstract

Background：Respiratory syncytial virus (RSV) is a leading cause of severe illness in infants, with no effective treatment. Results of a phase 2 trial suggested that ziresovir may have efficacy in the treatment of infants hospitalized with RSV infection.

Methods：In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted in China, we enrolled participants 1 to 24 months of age who were hospitalized with RSV infection. Participants were randomly assigned, in a 2:1 ratio, to receive ziresovir (at a dose of 10 to 40 mg, according to body weight) or placebo, administered twice daily, for 5 days. The primary end point was the change from baseline to day 3 (defined as 48 hours after the first administration) in the Wang bronchiolitis clinical score (total scores range from 0 to 12, with higher scores indicating greater severity of signs and symptoms). The intention-to-treat population included all the participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo; the safety population included all the participants who received at least one dose of ziresovir or placebo.

Results：The intention-to-treat population included 244 participants, and the safety population included 302. The reduction from baseline in the Wang bronchiolitis clinical score at day 3 was significantly greater with ziresovir than with placebo (−3.4 points [95% confidence interval {CI}, −3.7 to −3.1] vs. −2.7 points [95% CI, −3.1 to −2.2]; difference, −0.8 points [95% CI, −1.3 to −0.3]; P=0.002). The reduction in the RSV viral load at day 5 was greater in the ziresovir group than in the placebo group (−2.5 vs. −1.9 log10 copies per milliliter; difference, −0.6 log10 copies per milliliter [95% CI, −1.1 to −0.2]). Improvements were observed in prespecified subgroups, including in participants with a baseline bronchiolitis score of at least 8 and in those 6 months of age or younger. The incidence of adverse events related to the drug or placebo was 16% with ziresovir and 13% with placebo. The most common adverse events that were assessed by the investigator as being related to the drug or placebo were diarrhea (in 4% and 2% of the participants, respectively), an elevated liver-enzyme level (in 3% and 3%, respectively), and rash (in 2% and 1%). Resistance-associated mutations were identified in 15 participants (9%) in the ziresovir group.

Conclusions：Ziresovir treatment reduced signs and symptoms of bronchiolitis in infants and young children hospitalized with RSV infection. No safety concerns were identified.

背景：呼吸道合胞病毒（RSV）是婴儿严重疾病的主要原因，没有有效的治疗方法。一项2期试验的结果表明，齐来索韦可能对因RSV感染住院的婴儿具有疗效。

方法：在中国进行的III期、多中心、双盲、随机、安慰剂对照试验中，研究者招募了因RSV感染住院的1至24个月的受试者。参与者以2：1的比例随机分配接受ziresovir（剂量为10至40 mg，根据体重）或安慰剂，每天两次，持续5天。主要终点是Wang毛细支气管炎临床评分从基线到第3天（定义为首次给药后48小时）的变化（总评分范围为0 - 12，评分越高表示体征和症状的严重程度越高）。意向治疗人群包括所有接受过至少一剂齐来索韦或安慰剂治疗的RSV确诊感染受试者;安全性人群包括所有接受过至少一剂齐来索韦或安慰剂治疗的受试者

结果：意向治疗人群包括244名参与者，安全性人群包括302名参与者。Ziresovir组第3天Wang细支气管炎临床评分较基线的下降幅度显著大于安慰剂组（-3.4分vs.-2.7分）。第5天，齐瑞索韦组RSV病毒载量的下降幅度大于安慰剂组（-2.5 vs.-1.9 log10拷贝/毫升）。在预先指定的亚组中观察到改善，包括基线毛细支气管炎评分至少为8的参与者和6个月或更小的参与者。与药物或安慰剂相关的不良事件的发生率在齐瑞索韦组为16%，安慰剂组为13%。 被研究者评估为与药物或安慰剂相关的最常见不良事件为腹泻（分别为4%和2%的受试者）、肝酶水平升高（分别为3%和3%）和皮疹（分别为2%和1%）。在ziresovir组的15名参与者（9%）中确定了耐药相关突变。

结论：Ziresovir治疗减少了因RSV感染住院的婴幼儿毛细支气管炎的体征和症状。未发现安全性问题。

14.Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B

Fidanacogene Elaprovec（菲达纳科吉内尔埃尔帕鲁维克）基因治疗成人血友病B

宾夕法尼亚大学医院

Abstract

Background：Fidanacogene elaparvovec, an adeno-associated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX variant (FIX-R338L/FIX-Padua), was associated with sustained factor IX activity in a phase 1–2a study.

Methods：We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×1011 vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed.

Results：Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of −3.15 episodes (95% CI, −5.46 to −0.83; P=0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed.

Conclusions：Fidanacogene elaparvovec was superior to prophylaxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable factor IX expression.

背景：Fidanacogene elaparvovec是一种用于血友病B的腺相关病毒（AAV）基因治疗载体，含有高活性人因子IX变体（FIX-R338 L/FIX-Padua），在1-2a期研究中与持续的因子IX活性相关。

方法：研究者开展了一项III期开放标签研究，评估了fidanacogene elaparvovec治疗效果，剂量为每千克体重5×10¹¹载体基因组拷贝。18至65岁之间、患有B型血友病且IX因子水平为2%或以下的男性，如果在筛选时已接受至少6个月的预防性IX因子浓缩物治疗，符合入组标准。主要终点是测试非劣效性的年化出血率（包括治疗性和非治疗性出血事件），评估时间为治疗后第12周至第15个月，与预防性治疗引导期进行比较。还评估了优越性、其他疗效终点以及安全性。

结果：在316名接受导入研究筛选的男性中，204名（64.6%）不合格;其中188名（59.5%）由于存在抗AAV中和抗体而不合格。在接受fidanacogene elaparvovec的45名参与者中，44名完成了至少15个月的随访。所有出血事件的年出血率降低了71%，从基线时的4.42降至基因治疗后的1.28，治疗差异为-3.15次。该结果显示了非达纳基elaparvovec预防的非劣效性和优效性。在15个月时，通过一期SynthASil测定，平均因子IX活性为26.9%（中位数，22.9%;范围，1.9 - 119.0）。共有28名参与者（62%）在11至123天之间开始接受糖皮质激素治疗转氨酶水平升高或因子IX水平降低（或两者兼而有之）。未观察到输注相关严重不良事件、血栓形成事件、因子IX抑制物的形成或恶性疾病。

结论：Fidanacogene elaparvovec在治疗血友病B参与者方面优于预防性治疗，导致出血减少和因子IX表达稳定。

15.Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis

抗TL 1A单克隆抗体Tulisokibart治疗溃疡性结肠炎的II期试验

西奈山伊坎医学院

Abstract

Background：Tulisokibart is a tumor necrosis factor–like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response.

Methods：We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses.

Results：In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI], 14 to 37; P<0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI, 2 to 38; P=0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity.

Conclusions：In this short-term trial, tulisokibart was more effective than placebo in inducing clinical remission in patients with moderately to severely active ulcerative colitis. 

背景：Tulisokibart是一种正在开发的肿瘤坏死因子样细胞因子1A（TL 1A）单克隆抗体，用于治疗中度至重度活动性溃疡性结肠炎。设计了一种基于遗传学的诊断测试，以识别反应可能性增加的患者。

方法：将糖皮质激素依赖或溃疡性结肠炎常规或高级治疗失败的患者随机分配接受静脉注射tulisokibart（第1天1000 mg，第2、6和10周500 mg）或安慰剂。队列1包括患者，无论其缓解可能性检验的状态如何。队列2仅包括缓解可能性检测结果为阳性的患者。主要分析在队列1中进行;主要终点是第12周的临床缓解。在预先规定的分析中合并队列1和队列2中缓解可能性检测结果为阳性的患者。

结果：共有135例患者接受了随机化。接受tulisokibart治疗的患者临床缓解的百分比显著高于接受安慰剂治疗的患者（26% vs. 1%）。在队列2中，共有43例患者接受了随机化。两个队列中共有75例缓解可能性检测结果为阳性的患者接受了随机化。在反应可能性检测阳性的患者中（队列1和2合并），接受tulisokibart的患者发生临床缓解的百分比高于接受安慰剂的患者（32% vs. 11%）。在所有入组的患者中，tulisokibart组和安慰剂组的不良事件发生率相似;大多数不良事件的严重程度为轻度至中度。

结论：这项短期试验中，tulisokibart在诱导中度至重度活动性溃疡性结肠炎患者临床缓解方面比安慰剂更有效

16.Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women

半年两次注射的Lenacapavir与每日口服F/TAF用于顺性别女性的HIV预防

吉利德科学公司

Abstract

Background：There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women.

Methods：We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF.

Results：Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P=0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions.

Conclusions：No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF.

背景：在顺性别女性中，暴露前预防（PrEP）在HIV预防中的使用、依从性和持续性存在一定的差距。

方法：进行了一项3期、双盲、随机、对照试验，涉及南非和乌干达的少女和年轻妇女。参与者以2：2：1的比例被分配接受皮下注射来那卡韦，每26周一次，每日口服恩曲他滨-替诺福韦艾拉酚胺（F/TAF），或每日口服恩曲他滨-富马酸替诺福韦二异山梨酯（F/TDF;活性对照）;所有参与者还接受替代的皮下或口服安慰剂。研究者通过比较HIV感染的发生率与筛查人群中估计的背景发生率来评估Lenacapavir和F/TAF的疗效，并评价与F/TDF相比的相对疗效。

结果：在最初HIV阴性的5338名参与者中，观察到55例HIV感染事件：Lenacapavir组2134名参与者中0例感染（0/100人-年），F/TAF组2136例受试者中有39例感染（2.02/100人-年），F/TDF组1068例受试者中有16例感染（1.69/100人-年）。背景HIV在筛查人群（8094例受试者）中的发病率为2.41/100人-年。Lenacapavir组的HIV发病率显著低于背景HIV发病率（发病率比，0.00），注射部位反应在Lenacapavir组（68.8%）比安慰剂注射组（F/TAF和F/TDF合并）（34.9%）更常见; Lenacapavir组4名受试者（0.2%）因注射部位反应而中止试验方案。

结论：没有接受每年两次Lenacapavir的参与者获得HIV感染。Lenacapavir的HIV发生率显著低于背景HIV发生率和F/TDF的HIV发生率。

17.Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity

替扎帕肽治疗阻塞性睡眠呼吸暂停和肥胖症

加州大学圣地亚哥分校

Abstract

Background：Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.

Methods：We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea–hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure.

Results：At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was −25.3 events per hour (95% confidence interval [CI], −29.3 to −21.2) with tirzepatide and −5.3 events per hour (95% CI, −9.4 to −1.1) with placebo, for an estimated treatment difference of −20.0 events per hour (95% CI, −25.8 to −14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was −29.3 events per hour (95% CI, −33.2 to −25.4) with tirzepatide and −5.5 events per hour (95% CI, −9.9 to −1.2) with placebo, for an estimated treatment difference of −23.8 events per hour (95% CI, −29.6 to −17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity.

Conclusions：Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes.

背景：阻塞性睡眠呼吸暂停的特征是睡眠期间呼吸紊乱，并与主要的心血管并发症有关;过度肥胖是一个病因风险因素。Tirzepatide可能是一种潜在的治疗方法。

方法：两项3期、双盲、随机、对照试验，涉及患有中度至重度阻塞性睡眠呼吸暂停和肥胖的成年人。基线时未接受气道正压通气（PAP）治疗的参与者入组试验1，基线时接受PAP治疗的参与者入组试验2。参与者以1：1的比例被分配接受最大耐受剂量的替泽帕肽（10 mg或15 mg）或安慰剂，持续52周。主要终点是呼吸暂停低通气指数（AHI，睡眠一小时内呼吸暂停和低通气的数量）相对于基线的变化。关键的多重对照次要终点包括AHI和体重的百分比变化，缺氧负荷的变化，患者报告的睡眠损害和障碍，高敏C反应蛋白（hsCRP）浓度和收缩压。

结果：基线时，试验1和试验2的平均AHI分别为每小时51.5起事件和49.5起事件，平均体重指数（BMI，体重（千克）除以身高（米）的平方）分别为39.1和38.7。在试验1中，第52周时，与安慰剂组相比，替瑞帕肽组AHI的平均变化为每小时−25.3起事件，安慰剂组为每小时−5.3起事件，估计治疗差异为每小时−20.0起事件。最常报告的替瑞帕肽不良事件为胃肠道不良事件，严重程度大多为轻度至中度。

结论：在中度至重度阻塞性睡眠呼吸暂停和肥胖患者中，替瑞帕提降低了AHI、体重、缺氧负荷、hsCRP浓度和收缩压，并改善了睡眠相关的患者报告结局。

18.Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer

肌层浸润性膀胱癌的标准或扩大淋巴结切除术

贝勒医学院斯科特泌尿科

Abstract

Background：Whether extended lymphadenectomy is associated with improved disease-free and overall survival, as compared with standard lymphadenectomy, among patients with localized muscle-invasive bladder cancer undergoing radical cystectomy is unclear.

Methods：We randomly assigned, in a 1:1 ratio, patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2) to undergo bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes. Randomization was performed during surgery and stratified according to the receipt and type of neoadjuvant chemotherapy, tumor stage (T2 vs. T3 or T4a), and a Zubrod’s performance-status score (0 or 1 vs. 2; assessed on a 5-point scale, with higher scores indicating greater disability). The primary outcome was disease-free survival. Overall survival and safety were also assessed.

Results：Of 658 patients who were enrolled, 592 eligible patients were randomly assigned to undergo extended lymphadenectomy (292 patients) or standard lymphadenectomy (300). Surgery was performed by 36 surgeons at 27 sites in the United States and Canada. Neoadjuvant chemotherapy had been received by 57% of the patients. At a median follow-up of 6.1 years, recurrence or death had occurred in 130 patients (45%) in the extended-lymphadenectomy group and in 127 (42%) in the standard-lymphadenectomy group, and the estimated 5-year disease-free survival was 56% and 60%, respectively (hazard ratio for recurrence or death, 1.10; 95% confidence interval [CI], 0.86 to 1.40; P=0.45). Overall survival at 5 years was 59% in the extended-lymphadenectomy group and 63% in the standard-lymphadenectomy group (hazard ratio for death, 1.13; 95% CI, 0.88 to 1.45). Adverse events of grade 3 to 5 occurred in 157 patients (54%) in the extended-lymphadenectomy group and in 132 (44%) in the standard-lymphadenectomy group; death within 90 days after surgery occurred in 19 patients (7%) and 7 patients (2%), respectively.

Conclusions：As compared with standard lymphadenectomy, extended lymphadenectomy did not result in improved disease-free or overall survival among patients with muscle-invasive bladder cancer undergoing radical cystectomy and was associated with higher perioperative morbidity and mortality.

背景：在接受根治性膀胱切除术的局部肌层浸润性膀胱癌患者中，与标准淋巴结切除术相比，扩大淋巴结切除术是否与改善无病生存率和总生存率相关尚不清楚。

方法：以1：1的比例将临床分期为T2（局限于肌肉）至T4 a（侵犯邻近器官）的局限性肌肉浸润性膀胱癌患者随机分配，其中有两个或两个以下阳性淋巴结（N 0，N1或N2）接受双侧标准淋巴结切除术（盆腔两侧淋巴结清扫）或扩大淋巴结切除术，包括髂总淋巴结，坐骨神经前淋巴结和骶前淋巴结切除术。在手术期间进行随机化，并根据接受新辅助化疗和新辅助化疗的类型、肿瘤分期（T2与T3或T4 a）和Zubrod体能状态评分（0或1与2;采用5分制评估，评分越高表示残疾越大）进行分层。主要结局是无病生存期。还评估了总生存期和安全性。

结果：在入组的658例患者中，592例符合条件的患者被随机分配接受扩大淋巴结切除术（292例患者）或标准淋巴结切除术（300例）。手术由美国和加拿大27个研究中心的36名外科医生进行。57%的患者接受了新辅助化疗。中位随访时间为6.1年，扩大淋巴结切除术组和标准淋巴结切除术组分别有130例（45%）和127例（42%）患者复发或死亡，估计5年无病生存率分别为56%和60%（复发或死亡的风险比，1.10）。扩大淋巴结切除术组的5年总生存率为59%，标准淋巴结切除术组为63%（死亡风险比为1.13）。 扩大淋巴结切除术组和标准淋巴结切除术组分别有157例（54%）和132例（44%）患者发生3 - 5级不良事件;术后90天内死亡分别有19例（7%）和7例（2%）。

结论：与标准的淋巴结切除术相比，扩大的淋巴结切除术并没有改善接受根治性膀胱切除术的肌层浸润性膀胱癌患者的无病生存率或总生存率，并且与更高的围手术期发病率和死亡率相关。

19.Aggressive Lymphoma after CD19 CAR T-Cell Therapy

CD19 CAR T细胞治疗后的侵袭性淋巴瘤

德国戴塞尔多夫大学医院肿瘤中心

Summary：The development of a fatal, clonal, autonomously proliferating CD4−CD8− chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

总结：一名复发性原发性中枢神经系统淋巴瘤患者接受tisagenlecleucel治疗1个月后，发生了致死性、克隆性、自主增殖的CD4 - CD8 -嵌合抗原受体(CAR)+外周血t细胞淋巴瘤（PTCL）。PTCL具有克隆t细胞受体重排，这已经在CAR - t细胞制造的分离产物和7个月前的自体移植中检测到。在获得的离体标本中，CD34+干细胞及其后代的体细胞DNMT3A和TET2突变在PTCL中检测到。PTCL含有一个额外的体细胞TET2突变，在CAR - t细胞分离产物和最终的CAR - t细胞产物中已经以非常低的频率被检测到，这提供了克隆造血有助于淋巴瘤发生的证据。

20.Beta-Blocker Interruption or Continuation after Myocardial Infarction

心肌梗死后β受体阻滞剂中断或继续使用

法国索邦大学巴黎心脏病研究所

Abstract

Background：The appropriate duration of treatment with beta-blocker drugs after a myocardial infarction is unknown. Data are needed on the safety and efficacy of the interruption of long-term beta-blocker treatment to reduce side effects and improve quality of life in patients with a history of uncomplicated myocardial infarction.

Methods：In a multicenter, open label, randomized, noninferiority trial conducted at 49 sites in France, we randomly assigned patients with a history of myocardial infarction, in a 1:1 ratio, to interruption or continuation of beta-blocker treatment. All the patients had a left ventricular ejection fraction of at least 40% while receiving long-term beta-blocker treatment and had no history of a cardiovascular event in the previous 6 months. The primary end point was a composite of death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for cardiovascular reasons at the longest follow-up (minimum, 1 year), according to an analysis of noninferiority (defined as a between-group difference of<3 percentage points for the upper boundary of the two-sided 95% confidence interval). The main secondary end point was the change in quality of life as measured by the European Quality of Life–5 Dimensions questionnaire.

Results：A total of 3698 patients underwent randomization: 1846 to the interruption group and 1852 to the continuation group. The median time between the last myocardial infarction and randomization was 2.9 years (interquartile range, 1.2 to 6.4), and the median follow-up was 3.0 years (interquartile range, 2.0 to 4.0). A primary-outcome event occurred in 432 of 1812 patients (23.8%) in the interruption group and in 384 of 1821 patients (21.1%) in the continuation group (risk difference, 2.8 percentage points; 95% confidence interval [CI],<0.1 to 5.5), for a hazard ratio of 1.16 (95% CI, 1.01 to 1.33; P=0.44 for noninferiority). Beta-blocker interruption did not seem to improve the patients’ quality of life.

Conclusions：In patients with a history of myocardial infarction, interruption of long-term beta-blocker treatment was not found to be noninferior to a strategy of beta-blocker continuation.

背景：心肌梗死后β受体阻滞剂药物治疗的适当持续时间尚不清楚。需要关于中断长期β受体阻滞剂治疗的安全性和有效性的数据，以减少有无并发症心肌梗死病史的患者的副作用并改善其生活质量。

方法：在法国49个研究中心进行的一项多中心、开放标签、随机、非劣效性试验中，研究者将有心肌梗死病史的患者以1：1的比例随机分配至中断或继续β受体阻滞剂治疗组。所有患者在接受长期β受体阻滞剂治疗时左心室射血分数至少为40%，并且在过去6个月内没有心血管事件史。根据非劣效性分析（定义为双侧95%置信区间上限的组间差异<3个百分点），主要终点是最长随访（至少1年）时死亡、非致死性心肌梗死、非致死性卒中或因心血管原因住院的复合终点。 主要的次要终点是通过欧洲生活质量5维度问卷测量的生活质量的变化。

结果：共有3698例患者接受随机化：1846例进入中断组，1852例进入继续组。末次心肌梗死与随机分组之间的中位时间为2.9年，中位随访时间为3.0年。中断组1812例患者中有432例发生了主要结局事件（23.8%），持续组1821例患者中有384例（21.1%），在继续治疗组中（风险差异，2.8个百分点），风险比为1.16。β受体阻滞剂中断似乎没有改善患者的生活质量。

结论：对于有心肌梗死病史的患者，停止长期β-受体拮抗剂治疗未被证明优于继续使用β-受体拮抗剂的治疗策略。

21.Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy

脑肾上腺脑白质营养不良基因治疗后的血液肿瘤

波士顿儿童医院

Abstract

Background：Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear.

Methods：We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2–3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104.

Results：Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM–EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT.

Conclusions：Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. 

背景：用elivaldogene autotemcel（eli-cel）的基因疗法在治疗脑肾上腺脑白质营养不良的临床研究中显示出疗效，（eli-cel）由用含有ABCD 1互补DNA（Lenti-D）的慢病毒载体转导的自体CD 34+细胞组成。然而，eli-cel的肿瘤发生风险尚不清楚。

方法：在两项已完成的2-3期研究（ALD-102和ALD-104）和一项正在进行的随访研究（LTF-304）中接受eli-cel治疗的患者的外周血和骨髓样本中进行了整合位点分析、遗传学研究、流式细胞术和形态学研究，这些研究涉及ALD-102和ALD-104中的患者。

结果：在接受eli-cel治疗后，67例患者中有7例发生血液癌（ALD-102研究中32例患者中的1例和ALD-104研究中35例患者中的6例）：14和26个月时2例患者发生骨髓增生异常综合征（MDS）伴单系发育不良; 28、42和92个月时3例患者发生MDS伴原始细胞过多; 36个月时1例患者发生MDS; 57个月时1例患者发生急性髓性白血病（AML）。在6例有可用数据的患者中，主要克隆在多个位点包含慢病毒载体插入，包括MECOM-EVI 1（5例患者中的MDS和EVI 1复合蛋白EVI 1 [亲嗜性病毒整合位点1]）或PRDM 16（1例患者中的正调控结构域锌指蛋白16）。 几名患者出现血细胞减少，大多数患者在同一克隆内的多个基因中插入了载体; 7名患者中有6名还存在体细胞突变（KRAS、NRAS、WT 1、CDKN 2A或CDKN 2B或RUNX 1），7名患者中有1名存在单体7。在5例接受异基因造血干细胞移植（HSCT）的MDS伴原始细胞过多或MDS伴单系发育不良的患者中，4例患者在HSCT后20个月（接受eli-cel后49个月）仍无MDS，无脑肾上腺脑白质营养不良症状复发，1例患者死于假定的移植物抗宿主病。AML患者存活，并在HSCT后具有完全供体嵌合体;最近一例MDS患者存活，并等待HSCT。

结论：接受eli-cel治疗的一个亚组患者发生了血液癌;这些病例与癌基因内的克隆载体插入以及获得体细胞遗传缺陷的克隆进化有关。

22.Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy

脑肾上腺脑白质营养不良的慢病毒基因治疗

波士顿儿童医院

Abstract

Background：Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.

Methods：In a phase 2–3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score.

Results：A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up.

Conclusions：At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors.

背景：脑肾上腺脑白质营养不良是X连锁肾上腺脑白质营养不良的一种严重形式，其特征在于白质疾病、神经功能丧失和早期死亡。Elivaldogene autotemcel（eli-cel）基因疗法由用含有ABCD 1互补DNA的Lenti-D慢病毒载体转导的自体CD 34+细胞组成，正在脑肾上腺脑白质营养不良患者中进行测试。

方法：一项2-3期研究中，研究者评估了eli-cel治疗早期脑肾上腺脑白质营养不良和磁共振成像（MRI）活动性炎症证据的男孩的疗效和安全性。主要疗效终点是24个月时无任何六种主要功能障碍的生存率。次要终点包括第24个月的总生存率和总神经功能评分从基线到第24个月的变化。

结果：共有32名患者接受eli-cel; 29名患者（91%）完成了24个月的研究，并在长期随访研究中接受监测。在24个月时，这29名患者中没有一人有严重的功能障碍;总生存率为94%。在最近的评估（中位随访时间为6年）中，32例患者中有30例（94%）的神经功能评分与基线评分相比稳定; 26例患者（81%）无严重功能障碍。4名患者发生了与eli-cel直接相关的不良事件。第92个月时，1例患者发生骨髓增生异常综合征（MDS）伴原始细胞过多;该患者接受了异基因造血干细胞移植，最近一次随访时未发生MDS。

结论：慢病毒基因治疗后中位随访6年，大多数早期脑肾上腺脑白质营养不良和MRI异常的患者没有严重的功能障碍。然而，插入性致癌作用仍然是与病毒载体整合相关的持续风险。

23.Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer

度伐鲁单抗在局限期小细胞肺癌放化疗后的应用

阿姆斯特丹大学医学中心放射肿瘤科

Abstract

Background：Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy.

Methods：In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab–tremelimumab group remain blinded.

Results：A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab–tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P=0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P=0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group.

Conclusions：Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer.

背景：durvalumab联合或不联合曲美木单抗的辅助治疗可能对标准同步铂类放化疗后未出现疾病进展的局限期小细胞肺癌患者有效。

方法：一项3期、双盲、随机、安慰剂对照试验中，将患者分配为接受1500 mg剂量的durvalumab，durvalumab（1500 mg）+75 mg剂量的tremelimumab（仅4剂）或安慰剂，每4周一次，持续24个月。根据疾病分期（I或II vs. III）和是否接受预防性颅照射（是vs.否）对随机化进行分层。报告了durvalumab与安慰剂（数据截止日期：2024年1月15日）相比的两个主要终点（总生存期和无进展生存期）的首次计划中期分析结果（根据实体瘤疗效评价标准，第1.1版，基于设盲独立中心审查进行评估）; durvalumab-tremelimumab组的结果保持盲态。

结果：共有264名患者被分配到durvalumab组，200名患者分配到durvalumab-tremelimumab组，266名患者分配到安慰剂组。Durvalumab治疗导致总生存期显著长于安慰剂（中位数，55.9个月vs 33.4个月;死亡风险比，0.73），以及显著延长的无进展生存期（中位16.6个月vs 9.2个月;进展或死亡的风险比为0.76）。接受durvalumab治疗的患者和接受安慰剂治疗的患者中，最高等级为3或4级的不良事件发生率分别为24.4%和24.2%;分别有16.4%和10.6%的患者因不良事件停药，2.7%和1.9%的患者因不良事件死亡。肺部炎症或放射性肺炎3例，最高级别为3或4级。durvalumab组1%的患者和安慰剂组2.6%的患者。

结论：在局限期小细胞肺癌患者中，与安慰剂相比，durvalumab辅助治疗导致总生存期和无进展生存期显著延长。

24.Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma

Nivolumab（纳武单抗）+AVD治疗晚期经典型霍奇金淋巴瘤

罗彻斯特大学威尔莫特癌症研究所

Abstract

Background：Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin’s lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin’s lymphoma, including in preliminary studies involving previously untreated patients.

Methods：We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin’s lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause.

Results：Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P=0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.

Conclusions：N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin’s lymphoma and had a better side-effect profile.

背景：将维布妥昔单抗用于治疗晚期经典型霍奇金淋巴瘤可改善成人和儿童患者的结局。然而，维布妥昔单抗增加了成人治疗的毒性作用，超过一半的接受该药物的儿童患者接受了巩固放疗，复发仍然是一个挑战。程序性死亡1阻断在霍奇金淋巴瘤中有效，包括在涉及先前未经治疗的患者的初步研究中。

方法：一项III期、多中心、开放标签、随机试验，纳入了至少12岁的III期或IV期新诊断的霍奇金淋巴瘤患者。患者被随机分配接受维布妥昔单抗联合多柔比星、长春碱和达卡巴嗪（BV+AVD）或纳武单抗联合多柔比星、长春碱和达卡巴嗪（N+AVD）。预先指定的患者可以接受针对残留代谢活性病变的放射治疗。主要终点是无进展生存期，定义为从随机化到首次观察到疾病进展或任何原因导致的死亡的时间。

结果：在接受随机化的994例患者中，970例被纳入意向治疗人群进行疗效分析。在第二次计划的中期分析中，中位随访时间为12.1个月，越过了疗效阈值，表明与BV+AVD相比，N+AVD显著改善了无进展生存期（疾病进展或死亡的风险比，0.48）。由于随访时间较短，研究者重复了较长随访时间的分析;中位随访时间为2.1年，2年无进展生存率为92%，N+AVD组为83%，（疾病进展或死亡的风险比，0.45）。总体而言，7例患者接受了放射治疗。纳武利尤单抗组免疫相关不良事件不常见;维布妥昔单抗组与更多治疗中止相关。

结论：在患有III期或IV期晚期经典霍奇金淋巴瘤的青少年和成人中，N+AVD导致的无进展生存期长于BV+AVD，并且具有更好的副作用特征。

25.Safety of Kidney Transplantation from Donors with HIV

HIV感染者肾移植的安全性

约翰霍普金斯医学院

Abstract

Background：Kidney transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV is an emerging practice. It has been performed since 2016 under the U.S. congressional HIV Organ Policy Equity Act and is currently approved for research only. The Department of Health and Human Services is considering expanding the procedure to clinical practice, but data are limited to small case series that did not include donors without HIV as controls.

Methods：In an observational study conducted at 26 U.S. centers, we compared transplantation of kidneys from deceased donors with HIV and donors without HIV to recipients with HIV. The primary outcome was a safety event (a composite of death from any cause, graft loss, serious adverse event, HIV breakthrough infection, persistent failure of HIV treatment, or opportunistic infection), assessed for noninferiority (margin for the upper bound of the 95% confidence interval, 3.00). Secondary outcomes included overall survival, survival without graft loss, rejection, infection, cancer, and HIV superinfection.

Results：We enrolled 408 transplantation candidates, of whom 198 received a kidney from a deceased donor; 99 received a kidney from a donor with HIV and 99 from a donor without HIV. The adjusted hazard ratio for the composite primary outcome was 1.00 (95% confidence interval [CI], 0.73 to 1.38), which showed noninferiority. The following secondary outcomes were similar whether the donor had HIV or not: overall survival at 1 year (94% vs. 95%) and 3 years (85% vs. 87%), survival without graft loss at 1 year (93% vs. 90%) and 3 years (84% vs. 81%), and rejection at 1 year (13% vs. 21%) and 3 years (21% vs. 24%). The incidence of serious adverse events, infections, surgical or vascular complications, and cancer was similar in the groups. The incidence of HIV breakthrough infection was higher among recipients of kidneys from donors with HIV (incidence rate ratio, 3.14; 95%, CI, 1.02 to 9.63), with one potential HIV superinfection among the 58 recipients in this group with sequence data and no persistent failures of HIV treatment.

Conclusions：In this observational study of kidney transplantation in persons with HIV, transplantation from donors with HIV appeared to be noninferior to that from donors without HIV. 

背景：从携带人类免疫缺陷病毒（HIV）的供体向携带HIV的受体进行肾移植是一种新兴的做法。自2016年以来，它一直根据美国国会艾滋病毒器官政策公平法案进行，目前仅被批准用于研究。卫生与公众服务部正在考虑将该程序扩展到临床实践，但数据仅限于小病例系列，不包括未携带艾滋病毒的捐赠者作为对照。

方法：在美国26个中心进行的一项观察性研究中，研究者比较了来自感染艾滋病毒的已故捐赠者和未感染艾滋病毒的捐赠者的肾脏移植与感染艾滋病毒的接受者。主要结局为安全性事件（全因死亡、移植物丢失、严重不良事件、HIV突破性感染、HIV治疗持续失败或机会性感染的复合事件），评估非劣效性（95%置信区间上限的界值为3.00）。次要结局包括总生存率、无移植物丢失生存率、排斥反应、感染、癌症和HIV重叠感染。

结果：招募了408名移植候选人，其中198人接受了来自已故供体的肾脏; 99人接受了来自HIV供体的肾脏，99人接受了来自非HIV供体的肾脏。复合主要结局的校正风险比为1.00，显示非劣效性。无论供体是否感染HIV，以下次要结局相似：1年总生存率（94% vs. 95%）和3年（85% vs. 87%），1年时无移植物丢失的生存率（93% vs. 90%）和3年（84% vs. 81%），以及1年（13% vs. 21%）和3年（21% vs. 24%）时的排斥反应。两组严重不良事件、感染、手术或血管并发症以及癌症的发生率相似。HIV突破性感染的发生率在接受HIV供体肾脏的受者中更高（发病率比，3.14），在该组中的58名接受者中有一名潜在的HIV重叠感染者，有序列数据，并且没有HIV治疗的持续失败。

结论：在这项对HIV感染者进行肾移植的观察性研究中，来自HIV感染者的肾移植似乎不劣于来自无HIV感染者的肾移植。

26.A Modular Communicative Leadless Pacing–Defibrillator System

模块化通信无导线起搏-除颤器系统

阿姆斯特丹大学医学中心临床和实验心脏病学系

Abstract

Background：The subcutaneous implantable cardioverter–defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing–defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown.

Methods：We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker–defibrillator system. The safety end point was freedom from leadless pacemaker–related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%).

Results：We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker–related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure.

Conclusions：The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months.

背景：皮下植入式心律转复除颤器（ICD）与电极导线相关的并发症少于经静脉ICD;但是，皮下ICD不能提供心动过缓和抗心动过速起搏。模块化起搏除颤器系统是否安全仍不清楚，该系统包括与皮下ICD无线通信的无导线起搏器，以提供抗心动过速和心动过缓起搏。

方法：一项多国、单组研究，招募了有室性心律失常猝死风险的患者，并在植入模块化起搏器-除颤器系统后随访6个月。安全性终点是无无导线起搏器相关重大并发症，根据86%的性能目标进行评价。两个主要性能终点是起搏器和ICD之间的成功通信（性能目标，88%）和0.4 msec脉冲宽度下高达2.0 V的起搏阈值（性能目标，80%）。

结果：招募了293例患者，其中162例在6个月终点队列中，151例完成了6个月随访期。患者的平均年龄为60岁，16.7%为女性，平均（±SD）左心室射血分数为33.1± 12.6%。无无导线起搏器相关重大并发症的患者百分比为97.5%，超过了预先规定的性能目标。在98.8%的通信测试中，无线设备通信成功，超过了预先设定的目标。在151例患者中，147例（97.4%）的起搏阈值为2.0 V或更低，超过了预先规定的目标。抗心动过速起搏成功终止心律失常发作的百分比为61.3%，没有因通信故障而未提供抗心动过速起搏的事件。在162例患者中，8例死亡（4.9%）;认为这些死亡均与心律失常或植入手术无关。

结论：与皮下植入型心律转复除颤器（ICD）无线通信的无导线起搏器在多个方面超过了预期的性能目标，包括无导线起搏器相关的重大并发症发生率、无导线起搏器与皮下ICD之间的通信效果，以及在6个月时 pacing 阈值达到2.0V、0.4毫秒脉冲宽度的患者比例。

27.Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer

局部前列腺癌立体定向体部放疗的3期试验

英国皇家马斯登癌症中心

Abstract

Background：Whether stereotactic body radiotherapy (SBRT) is noninferior to conventionally or moderately hypofractionated regimens with respect to biochemical or clinical failure in patients with localized prostate cancer is unclear.

Methods：We conducted a phase 3, international, open-label, randomized, controlled trial. Men with stage T1 or T2 prostate cancer, a Gleason score of 3+4 or less, and a prostate-specific antigen (PSA) level of no more than 20 ng per milliliter were randomly assigned (in a 1:1 ratio) to receive SBRT (36.25 Gy in 5 fractions over a period of 1 or 2 weeks) or control radiotherapy (78 Gy in 39 fractions over a period of 7.5 weeks or 62 Gy in 20 fractions over a period of 4 weeks). Androgen-deprivation therapy was not permitted. The primary end point was freedom from biochemical or clinical failure, with a critical hazard ratio for noninferiority of 1.45. The analysis was performed in the intention-to-treat population.

Results：A total of 874 patients underwent randomization at 38 centers (433 patients in the SBRT group and 441 in the control radiotherapy group) between August 2012 and January 2018. The median age of the patients was 69.8 years, and the median PSA level was 8.0 ng per milliliter; the National Comprehensive Cancer Network risk category was low for 8.4% of the patients and intermediate for 91.6%. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% (95% confidence interval [CI], 93.3 to 97.4) in the SBRT group and 94.6% (95% CI, 91.9 to 96.4) in the control radiotherapy group (unadjusted hazard ratio for biochemical or clinical failure, 0.73; 90% CI, 0.48 to 1.12; P=0.004 for noninferiority), which indicated the noninferiority of SBRT. At 5 years, the cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects was 26.9% (95% CI, 22.8 to 31.5) with SBRT and 18.3% (95% CI, 14.8 to 22.5) with control radiotherapy (P<0.001), and the cumulative incidence of late RTOG grade 2 or higher gastrointestinal toxic effects was 10.7% (95% CI, 8.1 to 14.2) and 10.2% (95% CI, 7.7 to 13.5), respectively (P=0.94).

Conclusions：Five-fraction SBRT was noninferior to control radiotherapy with respect to biochemical or clinical failure and may be an efficacious treatment option for patients with low-to-intermediate-risk localized prostate cancer as defined in this trial. 

背景：在局限性前列腺癌患者的生化或临床失败方面，立体定向体部放疗（SBRT）是否不劣于常规或中度低分割方案尚不清楚。

方法：一项3期、国际、开放标签、随机、对照试验。患有T1或T2期前列腺癌，Gleason评分为3+4或更低，前列腺特异性抗原（PSA）水平不超过20 ng/ml的男性被随机分配（以1：1的比例）接受SBRT（36.25戈伊，分5次，为期1或2周）或对照放疗（78戈伊，分39次，为期7.5周或62戈伊，分20次，为期4周）。不允许雄激素剥夺治疗。主要终点是无生化或临床失败，非劣效性的临界风险比为1.45。在意向治疗人群中进行分析。

结果：2012年8月至2018年1月期间，共有874名患者在38个中心接受了随机分组（SBRT组433名患者，对照放疗组441名患者）。患者的中位年龄为69.8岁，中位PSA水平为8.0 ng/ml; 8.4%的患者的国家综合癌症网络风险类别为低，91.6%为中等。在中位随访74.0个月时，5年无生化或临床失败的发生率为95.8%SBRT组和94.6%对照组（生化或临床失败的未校正风险比，0.73;非劣效性P=0.004），表明SBRT的非劣效性。5年时，SBRT组晚期放射治疗肿瘤组（RTOG）2级或以上泌尿生殖系统毒性反应的累积发生率为26.9%，对照组为18.3%，晚期RTOG 2级或以上胃肠道毒性反应的累积发生率分别为10.7%和10.2%（P=0.94）。

结论：在生化或临床失败方面，五次SBRT不劣于对照放疗，可能是本试验中定义的低至中风险局限性前列腺癌患者的有效治疗选择。

28.Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

非那利酮在轻度降低或保留射血分数心力衰竭中的应用

波士顿布里格姆妇女医院心血管科

Abstract

Background；Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed.

Methods：In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed.

Results：Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P=0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P=0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia.

Conclusions：In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo.

背景：类固醇盐皮质激素受体拮抗剂可降低心力衰竭和射血分数降低患者的发病率和死亡率，但其在心力衰竭和射血分数轻度降低或保留患者中的疗效尚未确定。需要关于非甾体盐皮质激素受体拮抗剂非那利酮治疗射血分数轻度降低或保留的心力衰竭患者的疗效和安全性的数据。

方法：在这项国际双盲试验中，将心力衰竭和左心室射血分数为40%或更高的患者以1：1的比例随机分配，接受非那酮（最大剂量为20 mg或40 mg，每日一次）或匹配的安慰剂，除了常规治疗。主要结局是总体心力衰竭恶化事件（事件定义为首次或复发性计划外住院或因心力衰竭紧急访视）和心血管原因死亡的复合终点。还评估了主要结局和安全性的组成部分。

结果：在32个月的中位随访期内，非那酮组3003例患者中有624例发生了1083起主要结局事件，安慰剂组2998例患者中有719例发生了1283起主要结局事件（率比0.84; P=0.007）。非那利酮组和安慰剂组心力衰竭恶化事件总数分别为842和1024（率比，0.82; P=0.006）。死于心血管原因的患者百分比分别为8.1%和8.7%（风险比，0.93）。非那利酮与高钾血症风险增加和低钾血症风险降低相关。

结论：在心力衰竭和射血分数轻度降低或保留的患者中，与安慰剂相比，非那利酮导致总心力衰竭事件恶化和心血管原因死亡的复合发生率显著降低。

29.Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC

Amivantamab（阿米伐他单抗）联合Lazertinib（拉泽替尼）治疗既往未经治疗的EGFR突变晚期NSCLC

韩国首尔延世大学医学院延世癌症中心肿瘤内科

Abstract

Background：Amivantamab plus lazertinib (amivantamab–lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)–mutated advanced non–small-cell lung cancer (NSCLC).

Methods：In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab–lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab–lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review.

Results：Overall, 1074 patients underwent randomization (429 to amivantamab–lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab–lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab–lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab–lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab–lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab–lazertinib and 3% with osimertinib.

Conclusions：Amivantamab–lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. 

背景：在既往未经治疗或经奥希替尼预治疗的EGFR（表皮生长因子受体）突变晚期非小细胞肺癌（NSCLC）患者中，阿米伐他单抗联合lazertinib（amivantamab-lazertinib）显示出具有临床意义和持久的抗肿瘤活性。

方法：在一项III期、国际、随机试验中，研究者以2：2：1的比例将既往未接受治疗的EGFR突变（外显子19缺失或L 858 R）、局部晚期或转移性NSCLC患者分配接受amivantamab-lazertinib（以开放标签方式）、osimertinib（以设盲方式）或lazertinib（以设盲方式，评估治疗组分的贡献）。主要终点是amivantamab-lazertinib组与奥希替尼组相比的无进展生存期，通过盲法独立中心审查进行评估。

结果：1074例患者接受了随机化（429例接受amivantamab-lazertinib，429例接受osimertinib，216例接受lazertinib）。amivantamab-lazertinib组的中位无进展生存期显著长于奥希替尼组（23.7 vs. 16.6个月）。amivantamab-lazertinib组因治疗相关不良事件而停用所有药物的发生率为10%，奥希替尼组为3%。

结论：作为EGFR突变晚期NSCLC的一线治疗，阿米伐他单抗-lazertinib显示出优于奥希替尼的疗效。

30.Collagenase Injection versus Limited Fasciectomy for Dupuytren’s Contracture

胶原酶注射与限制性筋膜切除术治疗掌腱膜挛缩

英国莱斯特总医院肌肉骨骼外科

Abstract

Background：Treatments for Dupuytren’s contracture include limited fasciectomy and collagenase injection. Comparisons of the effectiveness of these treatments have been limited.

Methods：We performed an unblinded, multicenter, pragmatic, two-group, randomized, controlled noninferiority trial comparing collagenase injection with limited fasciectomy in persons with moderate Dupuytren’s contracture. The primary outcome was the score on the Patient Evaluation Measure–Hand Health Profile (PEM), a questionnaire for assessing hand health as reported by the patient, at 1 year after treatment. Scores on the PEM range from 0 to 100, with higher scores indicating worse outcomes. The prespecified noninferiority margin was 6 points.

Results：A total of 672 persons (336 per group) were assigned to receive collagenase injection or to undergo limited fasciectomy. The primary analysis included 599 persons: 314 in the collagenase group and 285 in the limited-fasciectomy group. The mean score on the PEM at 1 year was 17.8 among the 284 patients with available data in the collagenase group and 11.9 among the 250 patients with available data in the limited-fasciectomy group (estimated difference, 5.9 points; 95% confidence interval [CI], 3.1 to 8.8; one-sided P=0.49 for noninferiority). Among the patients with available data (229 patients in the collagenase group and 197 patients in the limited-fasciectomy group), the estimated difference in the mean score on the PEM at 2 years was 7.2 points (95% CI, 4.2 to 10.9). Moderate or severe complications of treatment occurred in 1.8% of the patients in the collagenase group and in 5.1% of those in the limited-fasciectomy group; recurrent contracture resulted in reintervention in 14.6% and 3.4%, respectively.

Conclusions：Collagenase injection was not noninferior to limited fasciectomy with respect to the score on the PEM at 1 year after treatment. 

背景：治疗Dupuytren掌腱膜挛缩包括限制性筋膜切除术和胶原酶注射。这些治疗方法的有效性比较有限。

方法：一项非盲、多中心、实用、两组、随机、对照的非劣效性试验，在中度掌腱膜挛缩患者中比较胶原酶注射与有限筋膜切除术。主要结果是患者评估测量手部健康状况（PEM）的评分，这是一份用于评估患者报告的手部健康状况的问卷，在治疗后1年。PEM的评分范围为0 - 100，评分越高表示结局越差。预先规定的非劣效性界值为6分。

结果：共有672人（每组336人）被分配接受胶原酶注射或接受有限的筋膜切除术。主要分析包括599人：胶原酶组314人，有限筋膜切除术组285人。胶原酶组中284例有可用数据的患者1年时PEM的平均评分为17.8分，限制性筋膜切除术组中250例有可用数据的患者1年时PEM的平均评分为11.9分（估计差异为5.9分）。在有可用数据的患者中（胶原酶组229例患者和限制性筋膜切除术组197例患者），2年时PEM平均评分的估计差异为7.2分。胶原酶组中1.8%的患者和有限筋膜切除术组中5.1%的患者发生中度或重度治疗并发症; 复发性挛缩导致再次干预分别为14.6%和3.4%。

结论：在治疗后1年的PEM评分方面，胶原酶注射并非优于限制性筋膜切除术。

31.Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene

lncRNA基因CHASERR缺失导致的神经发育障碍

波士顿儿童医院

Summary：CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination — a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. We found that the CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis. These findings indicate that CHD2 has bidirectional dosage sensitivity in human disease, and we recommend that other lncRNA-encoding genes be evaluated, particularly those upstream of genes associated with mendelian disorders.

主要内容：CHASERR编码一种位于CHD2旁边的人类长非编码RNA（lncRNA），CHD2是一种编码基因，其de novo功能丧失变异可引起发育性和癫痫性脑病。在这里，研究者报告了三名患有综合征性、早发性神经发育障碍的非亲缘儿童的研究发现，这些儿童每人都在CHASERR基因位点发生了de novo缺失。这些儿童表现出严重的脑病、共同的面部畸形、皮质萎缩和脑白质发育不良，这一表型与CHD2半合子缺失患者的表型有所不同。研究者发现CHASERR缺失导致患者来源的细胞系中CHD2蛋白丰度增加，并且CHD2转录本在顺式表达上升。这些发现表明，CHD2在人体疾病中具有双向剂量敏感性，我们建议对其他lncRNA编码基因进行评估，特别是那些位于与孟德尔遗传病相关基因上游的基因。

汇报人：李向东

导师：陈飞

审核：王肖宇、吴婷婷、任建君