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平滑肌肉瘤的多柔比星-trabectedin治疗及后续trabectedin维持治疗
Doxorubicin–Trabectedin with Trabectedin Maintenance in Leiomyosarcoma
背景
在晚期平滑肌肉瘤患者一线治疗中，多柔比星联合trabectedin治疗及后续trabectedin维持治疗的疗效可能优于多柔比星单药治疗。
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.
方法
我们对既往未接受过化疗的转移性或不可切除平滑肌肉瘤患者开展了一项3期试验。患者被随机分配接受多柔比星单药治疗（6个周期）或多柔比星联合trabectedin治疗（6个周期），多柔比星-trabectedin组中未出现疾病进展的患者继续接受trabectedin维持治疗。本试验允许两组患者在治疗6个周期后通过手术切除残留病变。无进展生存期（主要终点）和总生存期（次要终点）分析根据两项分层因素进行校正：肿瘤起源部位（子宫 vs. 软组织）和疾病分期（局部晚期 vs. 转移性）。主要终点结果此前已经发表。
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.
结果
共计150例患者接受随机分组。中位55个月随访时（四分位距，49~63），共计107例患者已死亡（多柔比星-trabectedin组47人，多柔比星组60人）。多柔比星-trabectedin组（33个月；95%置信区间[CI]，26~48）的中位总生存期超过多柔比星组（24个月；95% CI，19~31）；校正后的死亡风险比为0.65（95% CI，0.44~0.95）。与之前发表的结果一致，多柔比星-trabectedin组（12个月；95% CI，10~16）的无进展生存期超过多柔比星组（6个月；95% CI，4~7）；校正后的疾病进展或死亡风险比为0.37（95% CI，0.26~0.53）。多柔比星-trabectedin组的不良事件发生率和药物减量患者比例均高于多柔比星组。
Result
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.
结论
在转移性或不可切除的子宫或软组织平滑肌肉瘤患者中，多柔比星联合trabectedin诱导治疗及后续trabectedin维持治疗与多柔比星单药治疗相比，延长了总生存期和无进展生存期。（由PharmaMar公司等资助；LMS04在ClinicalTrials.gov注册号为NCT02997358）。
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. (Funded by PharmaMar and others; LMS04 ClinicalTrials.gov number, NCT02997358.)
PACAP单克隆抗体预防偏头痛
A Monoclonal Antibody to PACAP for Migraine Prevention
背景
以垂体腺苷酸环化酶激活多肽（PACAP）为靶点是治疗偏头痛的新途径。静脉注射LuAG09222（针对PACAP配体的人源化单克隆抗体）对偏头痛的预防效力和安全性尚未明确。
在一项2期、双盲、随机、安慰剂对照试验中，我们纳入了患偏头痛，且之前2~4种预防性治疗均未见效的成人参与者（18~65岁）。试验包括4周治疗期和8周随访期。以2:1:2比例将参与者随机分成三组，分别在基线时接受单剂750 mg LuAG09222、100 mg LuAG09222或安慰剂输注。主要终点是750 mg LuAG09222组与安慰剂组相比，第1~4周期间的每月偏头痛天数与基线相比的平均变化。
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.
在237名参与者中，97人接受了750 mg LuAG09222，46人接受了100 mg LuAG09222，94人接受了安慰剂。总体人群基线时的每月偏头痛平均天数为16.7天，第1~4周期间与基线相比的平均变化如下：750 mg LuAG09222组为－6.2天，而安慰剂组为－4.2天（差异，－2.0天；95%置信区间，－3.8~－0.3；P=0.02）。在12周观察期内，750 mg LuAG09222组发生率高于安慰剂组的不良事件包括COVID-19（7% vs. 3%）、鼻咽炎（7% vs. 4%）和疲劳（5% vs. 1%）。
Result
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%).
结论
在此项2期试验中，在降低用药后4周内的偏头痛频率方面，单次静脉注射750 mg LuAG09222的效果优于安慰剂。(由灵北制药资助；HOPE在ClinicalTrials.gov注册号为NCT05133323)。
静脉注射阿加曲班或依替巴肽用于缺血性卒中辅助治疗的比较
Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke
背景
静脉溶栓是急性缺血性卒中的标准治疗。静脉溶栓联合阿加曲班（抗凝剂）或依替巴肽（抗血小板药）的疗效和安全性尚未明确。
我们在美国57个研究中心开展了一项3期、三组、适应性、单盲、随机对照临床试验。在症状出现后3小时内接受静脉溶栓的急性缺血性卒中患者被分成三组，分别在溶栓开始后75分钟内接受静脉注射阿加曲班、依替巴肽或安慰剂。主要疗效结局是效用加权的90天改良Rankin量表评分（范围，0~10，评分较高表示结局较好）。此项结局通过集中裁定的方式评估。主要安全性结局是随机分组后36小时内发生有症状颅内出血。
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.
共计514例患者被分配接受阿加曲班（59人）、依替巴肽（227人）或安慰剂（228人）治疗。所有患者均接受了静脉溶栓（70%使用阿替普酶，30%使用替奈普酶），225例患者（44%）接受了血管内取栓术。90天时，阿加曲班组的效用加权改良Rankin量表平均（±SD）评分为5.2±3.7，依替巴肽组为6.3±3.2，安慰剂组为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Rankin量表评分的后验平均差，－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，－0.50±0.29）。三组患者的有症状颅内出血发生率相似（阿加曲班组4%，依替巴肽组3%，安慰剂组2%）。阿加曲班组（24%）和依替巴肽组（12%）的90天内死亡率高于安慰剂组（8%）。
Result
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%).
结论
在症状出现后3小时内接受静脉溶栓的急性缺血性卒中患者中，静脉注射阿加曲班或依替巴肽作为辅助治疗并不能减少卒中后残疾，并且死亡率提高。（由美国国立神经系统疾病和卒中研究所[National Institute of Neurological Disorders and Stroke]资助；MOST在ClinicalTrials.gov注册号为NCT03735979。）
一种与人类发热性疾病相关的新型正内罗病毒
A New Orthonairovirus Associated with Human Febrile Illness
背景
2019年6月，一例患者在中国内蒙古的一个湿地公园被蜱虫叮咬后出现持续发热和多器官功能障碍。通过对患者样本进行二代测序分析，发现其感染了一种此前未知的正内罗病毒（orthonairovirus），我们将其命名为湿地病毒（Wetland virus，WELV）。
为确定有蜱叮咬史的发热患者中WELV的流行情况，我们开展了基于医院的主动监测，并进行了流行病学调查，我们分离出病毒，并在动物模型中评估其感染性和致病性。
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.
WELV属于内罗病毒科（Nairoviridae）正内罗病毒属，与蜱传哈扎拉正内罗病毒基因群（Hazara orthonairovirus genogroup）关系最为密切。逆转录酶-聚合酶链反应检测结果表明，在中国内蒙古、黑龙江、吉林和辽宁共检测到17名WELV急性感染病例。这些患者表现出非特异性临床症状，包括发热、头晕、头痛、乏力、肌肉酸痛、关节炎和背痛，少数出现皮下瘀血点和局部淋巴结肿大。其中一名患者还出现神经系统症状。常见实验室检查异常结果包括白细胞减少、血小板减少，以及D-二聚体和乳酸脱氢酶水平升高。对8名患者的恢复期样本进行血清学评估，显示WELV特异性抗体滴度达到急性期样本滴度4倍以上。从中国东北地区采集到的5种蜱虫，以及绵羊、马、猪和东北鼢鼠标本中均检测到WELV RNA。从指示病例和蜱中分离到WELV，发现该病毒感染人脐静脉内皮细胞可引发细胞病变效应。经腹腔注射WELV后，BALB/c、C57BL/6和昆明种鼠均出现致死性感染。嗜群血蜱（Haemaphysalis concinna）可能是能够经卵传播WELV的潜在媒介。
Result
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.
结论
本研究发现了一种新的正内罗病毒，并证实其与中国东北地区的人类发热性疾病相关。（本研究由国家自然科学基金委和中国医学科学院医学科学创新基金资助）。
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