2023年3月30日 |《新英格兰医学杂志》英文音频和中英文摘要

英文音频来自NEJM官网nejm.org

1

阿奇霉素预防计划经阴道分娩产妇的脓毒症或死亡

Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth

摘 要

背景

阿奇霉素可以降低计划外剖宫产产妇的感染风险，但对计划经阴道分娩产妇的影响尚不清楚。我们需要了解产程中口服阿奇霉素能否降低产妇和后代的脓毒症或死亡风险。

Background

The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death.

方法

在这项国际性、安慰剂对照、随机试验中，我们将孕周≥28并计划经阴道分娩的产妇分组，分别口服阿奇霉素2 g或安慰剂。两项主要结局是由产妇脓毒症或死亡构成的复合结局，以及由死产或者新生儿死亡或脓毒症构成的复合结局。在期中分析中，数据和安全监查委员会建议，为了产妇的利益，停止该试验。

Methods

In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks’ gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit.

结果

共计29,278名产妇接受了随机分组。阿奇霉素组的产妇脓毒症或死亡发生率低于安慰剂组（1.6% vs. 2.4%），相对危险度为0.67（95%置信区间[CI]，0.56~0.79；P<0.001），但死产或者新生儿死亡或脓毒症的发生率相似（10.5% vs. 10.3%），相对危险度为1.02（95% CI，0.95~1.09；P=0.56）。产妇主要结局的差异似乎主要源于脓毒症发生率（阿奇霉素组为1.5%，安慰剂组为2.3%），相对危险度为0.65（95% CI，0.55~0.77）；两组的全因死亡率均为0.1%（相对危险度，1.23；95% CI，0.51~2.97）。新生儿脓毒症发生率分别为9.8% vs. 9.6%（相对危险度，1.03；95% CI，0.96~1.10）。两组死产发生率均为0.4%（相对危险度，1.06；95% CI，0.74~1.53）；两组出生后4周内的新生儿死亡率均为1.5%（相对危险度，1.03；95% CI，0.86~1.24）。阿奇霉素组的不良事件发生率并未高于安慰剂组。

Result

A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P=0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events.

结论

在计划经阴道分娩的产妇中，单次口服阿奇霉素使产妇脓毒症或死亡风险显著低于安慰剂，但对新生儿脓毒症或死亡的影响很小。(由尤尼斯·肯尼迪·施莱佛国立儿童健康与人类发展研究所[Eunice Kennedy Shriver National Institute of Child Health and Human Development]等资助；A-PLUS在ClinicalTrials.gov注册号为NCT03871491）。

Conclusions

Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.)

lan T.N. Tita, Waldemar A. Carlo, Elizabeth M. McClure, Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. DOI:10.1056/NEJMoa2212111

2

慢性严重肢体缺血的经导管深静脉动脉化治疗

Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia

摘 要

背景

约20%的慢性严重肢体缺血患者没有可供血运重建的血管，因此需要在脚踝以上水平截肢。经导管深静脉动脉化是一种经皮治疗方法，可以连通动脉与静脉，通过静脉系统向缺血的脚部输送含氧血液，从而避免截肢。

Background

Approximately 20% of patients with chronic limb-threatening ischemia have no revascularization options, leading to above-ankle amputation. Transcatheter arterialization of the deep veins is a percutaneous approach that creates an artery-to-vein connection for delivery of oxygenated blood by means of the venous system to the ischemic foot to prevent amputation.

方法

我们开展了一项前瞻性、单组、多中心研究，纳入溃疡不愈合且没有手术或血管内血运重建治疗机会的患者，以评估经导管深静脉动脉化的疗效。复合主要终点是6个月内无截肢生存率（定义为未发生脚踝以上水平截肢或任何原因死亡），操作性目标（performance goal）设为54%。次要终点包括肢体挽救、伤口愈合和手术取得技术成功。

Methods

We conducted a prospective, single-group, multicenter study to evaluate the effect of transcatheter arterialization of the deep veins in patients with nonhealing ulcers and no surgical or endovascular revascularization treatment options. The composite primary end point was amputation-free survival (defined as freedom from above-ankle amputation or death from any cause) at 6 months, as compared with a performance goal of 54%. Secondary end points included limb salvage, wound healing, and technical success of the procedure.

结果

我们招募了105名慢性严重肢体缺血患者，中位年龄为70岁（四分位距，38~89）。在纳入的患者中，33人（31.4%）为女性，45人（42.8%）为黑种人、西班牙语裔或拉丁裔。104名患者（99.0%）成功进行了经导管深静脉动脉化手术。6个月时，无截肢生存率为66.1%。根据贝叶斯分析，6个月时无截肢生存率超过54%操作性目标的后验概率为0.993，超过了预先设定的0.977阈值。67名患者实现了肢体挽救（避免了脚踝以上水平的截肢）（Kaplan-Meier分析结果为76.0%）。63名患者中有16名（25%）的伤口完全愈合，63名患者中有32名（51%）的伤口正在愈合中。未报告意料之外的设备相关不良事件。

Result

We enrolled 105 patients who had chronic limb-threatening ischemia and were of a median age of 70 years (interquartile range, 38 to 89). Of the patients enrolled, 33 (31.4%) were women and 45 (42.8%) were Black, Hispanic, or Latino. Transcatheter arterialization of the deep veins was performed successfully in 104 patients (99.0%). At 6 months, 66.1% of the patients had amputation-free survival. According to Bayesian analysis, the posterior probability that amputation-free survival at 6 months exceeded a performance goal of 54% was 0.993, which exceeded the prespecified threshold of 0.977. Limb salvage (avoidance of above-ankle amputation) was attained in 67 patients (76.0% by Kaplan–Meier analysis). Wounds were completely healed in 16 of 63 patients (25%) and were in the process of healing in 32 of 63 patients (51%). No unanticipated device-related adverse events were reported. 

结论

我们发现，在慢性严重肢体缺血且缺乏常规手术或血管内治疗方案的患者中，经导管深静脉动脉化治疗是安全的，而且可以成功实施。(由LimFlow资助；PROMISE II在ClinicalTrials.gov注册号为NCT03970538。)

Conclusions

We found that transcatheter arterialization of the deep veins was safe and could be performed successfully in patients with chronic limb-threatening ischemia and no conventional surgical or endovascular revascularization treatment options. (Funded by LimFlow; PROMISE II study ClinicalTrials.gov number, NCT03970538.)

Mehdi H. Shishehbor, Richard J. Powell, Miguel F. Montero-Baker,Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia. DOI:10.1056/NEJMoa2212754

3

幽门螺杆菌、同源重组基因和胃癌的关系

Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer

摘 要

背景

幽门螺杆菌感染是众所周知的胃癌危险因素。然而，癌症易感基因的胚系致病变异体以及它们与幽门螺杆菌感染同时存在时对胃癌风险的影响尚未广泛评估。

Background

Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated.

方法

我们纳入日本生物样本库（BioBank Japan）中的10,426例胃癌患者和38,153例对照样本，评估了27个癌症易感基因的胚系致病变异体与胃癌风险之间的关联。我们还评估了致病变异体和幽门螺杆菌感染状态对胃癌风险的复合效应，并在爱知癌症中心基于医院的流行病学研究项目（Hospital-based Epidemiologic Research Program at Aichi cancer Center，HERPACC）的1,433例胃癌患者和5,997例对照中计算了累积风险。

Methods

We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC).

结果

9个基因（APC、ATM、BRCA1、BRCA2、CDH1、MLH1、MSH2、MSH6和PALB2）的胚系致病变异体与胃癌风险相关。在HERPACC样本中，我们发现在胃癌风险方面，幽门螺杆菌感染和同源重组基因的致病变异体之间存在交互作用（交互作用导致的相对超额危险度，16.01；95%置信区间[CI]， 2.22~29.81；P=0.02）。在85岁时，有致病变异体的幽门螺杆菌感染者的胃癌累积风险高于感染幽门螺杆菌的非致病变异体携带者（45.5% [95% CI，20.7~62.6] vs. 14.4% [95% CI，12.2~16.6]）。

Result

Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P=0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]).

结论

幽门螺杆菌感染改变了与同源重组基因胚系致病变异体相关的胃癌风险。（由日本医学研究与发展机构[Japan Agency for Medical Research and Development]等资助。）

Conclusions

H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.)

Yoshiaki Usui, Yukari Taniyama, Mikiko Endo,Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. DOI:10.1056/NEJMoa2211807

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4

维得利珠单抗治疗慢性贮袋炎

Vedolizumab for the Treatment of Chronic Pouchitis

摘 要
背景在接受全结直肠切除回肠贮袋肛管吻合手术（IPAA）治疗的溃疡性结肠炎患者中，大约一半的患者随后会出现贮袋炎，其中五分之一患者会出现慢性贮袋炎。BackgroundApproximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis.
方法我们开展了一项4期双盲随机试验，纳入因溃疡性结肠炎接受IPAA手术后出现慢性贮袋炎的成人患者，对维得利珠单抗进行评估。患者被分配（按1:1的比例）在第1天和第2、6、14、22和30周静脉注射维得利珠单抗（300 mg）或安慰剂。所有患者在第1至4周同时接受环丙沙星治疗。主要终点是在第14周时，改良贮袋炎疾病活动指数（modified Pouchitis Disease Activity Index，mPDAI）定义的缓解（mPDAI评分≤4，并且mPDAI总分比基线减少≥2分；评分范围为0~12，评分越高表明贮袋炎越严重）。mPDAI根据临床症状和内镜检查结果评估。其他疗效终点包括第34周mPDAI定义的缓解，第14周和第34周mPDAI定义的应答（mPDAI评分比基线减少≥2分），以及第14周和第34周PDAI定义的缓解（PDAI评分≤6且比基线减少≥3分；评分范围为0~18，评分越高表示贮袋炎越严重）。PDAI基于临床症状、内镜检查结果和组织学检查结果评估。MethodsWe conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)–defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings. 
结果在接受随机分组的102例患者中，维得利珠单抗组第14周mPDAI定义的缓解率为31%（16/51），安慰剂组为10%（5/51）（差异，21个百分点；95%置信区间[CI]，5~38；P=0.01）。在下列终点的差异方面，维得利珠单抗均优于安慰剂：第34周mPDAI定义的缓解（差异，17个百分点；95% CI，0~35），第14周（差异，30个百分点；95% CI，8~48）和第34周（差异，22个百分点；95% CI，2~40）mPDAI定义的应答，以及第14周（差异，25个百分点；95% CI，8~41）和第34周（差异，19个百分点；95% CI，2~37）PDAI定义的缓解。维得利珠单抗组51例患者中有3例（6%）发生严重不良事件，安慰剂组51例患者中有4例（8%）发生严重不良事件。ResultAmong the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P=0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group.
结论对于因溃疡性结肠炎接受IPAA治疗后的慢性贮袋炎患者，与安慰剂相比，维得利珠单抗治疗能更有效地诱导缓解。(由武田制药资助；EARNEST在ClinicalTrials.gov注册号为NCT02790138；在EudraCT注册号为2015-003472-78）。ConclusionsTreatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.)

Simon Travis, Mark S. Silverberg, Silvio Danese,Vedolizumab for the Treatment of Chronic Pouchitis. DOI:10.1056/NEJMoa2208450

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