原创 刘敏 华西医院耳鼻喉科
华西耳鼻喉前沿学术速递——文献导读（第61期）
【The New England Journal of Medicine】2024年11-12月刊论文导读
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所出版的世界一流的综合性医学期刊。发表与各医学专业相关的研究，以及关于医学伦理、公共卫生和医疗政策的文章。文章类型主要是临床研究、综述、病例报告和社论等。这一期刊对生物医学科学与临床实践具有重要意义。该刊创刊于1812年，为周刊，最新影响因子为158.5。本期文献导读将呈现2024年11月至2024年12月上旬的主要刊物内容。
November 7, 2024; Volume 391 (18): 1665-1760
在2024年11月7日，共发表20篇文章，其中包括3篇Perspective，4篇Original articles，1篇Clinical Practice，1篇Videos in Clinical Medicine，2篇Images in clinical medicine，1篇Clinical problem-solving，4篇Editorials，1篇Sounding Board，3篇Correspondence。
1.Invasive Treatment Strategy for Older Patients with Myocardial Infarction
AFFILIATIONS
From the Translational and Clinical Research Institute, Faculty of Medical Sciences (V.K.), the Population Health Sciences Institute (H.M., M.D.T.), and the Newcastle Clinical Trials Unit (C.S., M. Bardgett, P.W., M.D.T., J.P.), Newcastle University, and the Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust (V.K., J.A.H., I.U.H.), Newcastle upon Tyne; Northumbria Healthcare NHS Foundation Trust, Cramlington (C.R., D.P.R.); the Faculty of Health Sciences and Wellbeing, School of Medicine, University of Sunderland Medical School, Sunderland (D.P.R.); North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (J. Carter, J.Q.); Chesterfield Royal Hospital, Chesterfield (J. Cooke); South Tees NHS Foundation Trust, Middlesbrough (D.A.); County Darlington and Durham NHS Foundation Trust, Darlington (J. Murphy); Royal Derby Hospital, Derby (D.K.); University Hospital Ayr, Ayr (J. McGowan); Leeds Teaching Hospital NHS Trust, Leeds (M.V.); Torbay and South Devon NHS Foundation Trust, Torquay (D.F.); Manchester University NHS Foundation Trust, Manchester (H.C.); Epsom and St. Helier University Hospitals, Epsom (S.M.); Ninewells Hospital, Dundee (J.I.); Bradford Royal Infirmary, Bradford (S.L.); Blackpool Victoria Hospital, Blackpool (G.G.); United Lincolnshire Hospitals NHS Trust, Lincoln (K.L.); Wrightington Wigan and Leigh Teaching Hospitals NHS Foundation Trust, Wigan (A.S.); North Bristol NHS Trust, Bristol (A.G.D.); University Hospital of Leicester NHS Trust, Leicester (S.H.); Barts Health NHS Trust (M. Belder) and London School of Hygiene and Tropical Medicine (S.J.P.), London; the Centre for Cardiovascular Science, University of Edinburgh, Edinburgh (M.D., D.E.N., K.A.A.F.); Norwich Medical School, University of East Anglia, Norwich (M.F.); and Sheffield Teaching Hospital, Sheffield (R.F.S.) — all in the United Kingdom.
Abstract
Background
Whether a conservative strategy of medical therapy alone or a strategy of medical therapy plus invasive treatment is more beneficial in older adults with non–ST-segment elevation myocardial infarction (NSTEMI) remains unclear.
Methods
We conducted a prospective, multicenter, randomized trial involving patients 75 years of age or older with NSTEMI at 48 sites in the United Kingdom. The patients were assigned in a 1:1 ratio to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization plus the best available medical therapy. Patients who were frail or had a high burden of coexisting conditions were eligible. The primary outcome was a composite of death from cardiovascular causes (cardiovascular death) or nonfatal myocardial infarction assessed in a time-to-event analysis.
Results
A total of 1518 patients underwent randomization; 753 patients were assigned to the invasive-strategy group and 765 to the conservative-strategy group. The mean age of the patients was 82 years, 45% were women, and 32% were frail. A primary-outcome event occurred in 193 patients (25.6%) in the invasive-strategy group and 201 patients (26.3%) in the conservative-strategy group (hazard ratio, 0.94; 95% confidence interval [CI], 0.77 to 1.14; P=0.53) over a median follow-up of 4.1 years. Cardiovascular death occurred in 15.8% of the patients in the invasive-strategy group and 14.2% of the patients in the conservative-strategy group (hazard ratio, 1.11; 95% CI, 0.86 to 1.44). Nonfatal myocardial infarction occurred in 11.7% in the invasive-strategy group and 15.0% in the conservative-strategy group (hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications occurred in less than 1% of the patients.
Conclusions
In older adults with NSTEMI, an invasive strategy did not result in a significantly lower risk of cardiovascular death or nonfatal myocardial infarction (the composite primary outcome) than a conservative strategy over a median follow-up of 4.1 years.
1.老年心肌梗死患者的侵入性治疗策略
背景
对于老年非ST段抬高型心肌梗死(NSTEMI)患者，单独采取药物治疗的保守策略，还是采取药物联合侵入性治疗的策略，目前仍不清楚哪种方式更有益。
方法
该研究在英国48个中心开展了一项前瞻性、多中心、随机试验，研究对象为75岁或以上的NSTEMI患者。患者按1:1的比例分配到最佳药物治疗访蓉保守策略组，或侵入性策略组（冠状动脉造影和血运重建加最佳药物治疗）。体弱或合并症较重的患者也被纳入进来。主要结局是心血管原因导致的死亡（心血管死亡）或非致死性心肌梗死的复合结局，采用事件发生时间分析。
结果
共纳入了1518例患者，其中753人被分配到侵入组，765人被分配到保守组。患者的平均年龄为82岁，45%为女性，32%存在虚弱状态。中位随访4.1年期间，侵入组有193名患者（25.6%）发生了主要结局事件，保守组有201名患者（26.3%）发生了主要结局事件（风险比为0.94；95%置信区间[CI]为0.77 ~1.14；P=0.53）。侵入组中有15.8%的患者发生心血管死亡，保守组中有14.2%的患者发生心血管死亡（风险比为1.11；95% CI为0.86 ~ 1.44）。侵入组中有 11.7% 的患者发生了非致命性心肌梗死，保守组中有15.0%的患者发生了非致命性心肌梗死（风险比为0.75；95% CI为0.57 ~ 0.99）。手术并发症发生率不到1%。
结论
在中位随访4.1年期间，对于患有NSTEMI的老年人，相较于保守策略，侵入性治疗策略并没有显著降低心血管死亡或非致死性心肌梗死的复合结局风险。
2.Randomized Trial of Very Early Medication Abortion
AFFILIATIONS
From the Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology (K.B., K.G.-D.), and the Department of Clinical Sciences at Danderyd Hospital (H.K.K.), Karolinska Institutet, and the Department of Obstetrics and Gynecology, Karolinska University Hospital (K.G.-D.), Stockholm, Södertälje Hospital, Södertälje (K.B.), the Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg (T.J.-A., H.H.), the Department of Obstetrics and Gynecology, Skåne University Hospital, Malmö (P.T.), the Department of Clinical Sciences, Lund University Faculty of Medicine, Lund (P.T.), the Department of Clinical Sciences, Obstetrics, and Gynecology, Umeå University, Umeå (M.B.), and Statisticon, Uppsala (J.B.) — all in Sweden; the Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, and Chalmers Centre, NHS Lothian — both in Edinburgh (J.R.-W., S.C.); the Departments of Obstetrics and Gynecology (F.G., J.K., O.H.) and General Practice and Primary Health Care (F.G.), University of Helsinki and Helsinki University Hospital, Helsinki, and the Division of Health and Social Services, Wellbeing Services County of Vantaa and Kerava, Vantaa (F.G.) — both in Finland; the Center for Research on Environment, Health, and Population Activities, Kathmandu (A.T.), and KIST Medical College Teaching Hospital, Lalitpur (H.T.) — both in Nepal; Family Planning Australia, Sydney Medical School, University of Sydney, and the School of Public Health, University of Technology Sydney — all in Sydney (C.B.); Women’s Health, Auckland City Hospital, Auckland, New Zealand (K.S., G.G.); the Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway (M.L.); and the Department of Obstetrics and Gynecology, Copenhagen University Hospital Hvidovre, Hvidovre (M.M.K.), and the Hospital of Southern Jutland, Aabenraa (E.K.) — both in Denmark.
Abstract
Background
Medication abortion, with a combination of mifepristone and misoprostol, is highly effective and safe. However, there is insufficient evidence on efficacy and safety at very early gestations before a pregnancy can be visualized with ultrasonography.
Methods
We conducted a multicenter, noninferiority, randomized, controlled trial involving women requesting medication abortion at up to 42 days of gestation with an unconfirmed intrauterine pregnancy on ultrasound examination (visualized as an empty cavity or a sac-like structure without a yolk sac or embryonic pole). Participants were randomly assigned to either immediate start of abortion (early-start group) or standard-care treatment delayed until intrauterine pregnancy was confirmed (standard group). The primary outcome was complete abortion. The noninferiority margin was set at 3.0 percentage points for the absolute between-group difference.
Results
In total, 1504 women were included at 26 sites in nine countries and were randomly assigned to the early-start group (754 participants) or the standard group (750 participants). In an intention-to-treat analysis, a complete abortion occurred in 676 of 710 participants (95.2%) in the early-start group and in 656 of 688 (95.3%) in the standard group; the absolute between-group difference was −0.1 percentage points (95% confidence interval, −2.4 to 2.1). Ectopic pregnancies occurred in 10 of 741 participants (1.3%) in the early-start group and in 6 of 724 (0.8%) in the standard group, with one rupture before diagnosis (early-start group). Serious adverse events occurred in 12 of 737 participants (1.6%) in the early-start group and in 5 of 718 (0.7%) in the standard group (P=0.10); the majority were uncomplicated hospitalizations for treatment of ectopic pregnancy or incomplete abortion.
Conclusions
Medication abortion before confirmed intrauterine pregnancy was noninferior to standard, delayed treatment with respect to complete abortion.
2.极早期药物流产的随机对照试验
背景
药物流产（米非司酮和米索前列醇联合使用）非常有效且安全。然而，在超声检查无法发现妊娠的极早期妊娠阶段，使用药物流产的有效性和安全性证据尚不充分。
方法
该研究进行了一项多中心、非劣效性、随机对照试验，纳入了超声检查未确认宫内妊娠（表现为空腔或无卵黄囊或胚胎极的囊状结构），并在妊娠42天内要求药物流产的女性。参与者被随机分配到立即开始流产（早期开始组）或延迟到确认宫内妊娠后才进行标准护理治疗（标准组）。主要结局是完全流产。非劣效性界值设定为组间绝对差异的3.0个百分点。
结果
在9个国家的26个研究中心纳入的1,504名女性，被随机分配到早期开始组（754名参与者）或标准组（750名参与者）。在意向治疗分析中，早期开始组710名参与者中有676名（95.2%）完全流产，标准组688名参与者中有656名（95.3%）完全流产；组间绝对差异为-0.1个百分点（95% 置信区间，-2.4 ~ 2.1）。早期开始组741名参与者中有10 名（1.3%）发生了异位妊娠，标准组724名参与者中有6名（0.8%）发生了异位妊娠，其中一名在诊断前破裂（早期开始组）。早期开始组737名参与者中有12名（1.6%）出现了严重不良事件，标准组718名参与者中有5名（0.7%）出现了严重不良事件（P=0.10）；大多数是因治疗异位妊娠或流产不全而住院治疗。
结论
在完全流产方面，确认宫内妊娠前的药物流产不劣于标准的延迟治疗。
November 14, 2024; Volume 391 (19): 1761-1864
在2024年11月14日，共发表27篇文章，其中包括7篇Perspective，4篇Original articles，1篇Review Article，2篇Images in clinical medicine，1篇Interactive Medical Case，1篇Case Records of the Massachusetts General Hospital，6篇Editorials，1篇Health Policy Report，2篇Correspondence。
3.Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer
AFFILIATIONS
From Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust Biomedical Research Centre, London (T.P.), the Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (J.W.F.C.), and AstraZeneca, Cambridge (J.A.) — all in the United Kingdom; the Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (M.D.G.), the Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center (H.A.-A.), and AstraZeneca (A.G.) — all in New York; the Departments of Urology and Biochemistry, Northwestern University Feinberg School of Medicine, Chicago (J.J.M.); the University of Tsukuba, Tsukuba, Japan (H.N.); Internal Medical 3, Vietnam National Cancer Hospital, Hanoi (T.Q.V.); the Department of Experimental and Clinical Medicine, University of Florence, and the Medical Oncology Unit, Careggi University Hospital — both in Florence, Italy (L.A.); Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.W.); the Volga District Medical Center, Federal Medical-Biological Agency, Nizhny Novgorod, Russia (V.A.); Hospital Alemão Oswaldo Cruz, Sao Paulo (A.G.K.); the Department of Urology, Kyungpook National University Chilgok Hospital, Daegu, South Korea (T-H.K.); Medical Oncology, Vall d´Hebron Institute of Oncology, Hospital Universitari Vall d´Hebron, Vall d´Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Urology, China Medical University Hospital and School of Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan (C-H.C.); the Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany (F.R.); Istanbul University–Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey (M.Ö.); BC Cancer–Vancouver, Vancouver, BC, Canada (B.J.E.); Mater Hospital Brisbane, Mater Misericordiae, and the School of Clinical Medicine, Mater Clinical Unit, University of Queensland — both in Brisbane, Australia (N.O.); the Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic (T.B.); the Institute of Oncology, Sheba Medical Center, Ramat Gan, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv — both in Israel (M.G.); the University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Iowa City (Y.Z.); AstraZeneca, Gaithersburg, MD (S.H.); and the Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam (M.S.H.).
Abstract
Background
Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.
Methods
In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine–cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point.
Results
In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P=0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group.
Conclusions
Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone.
3.可手术膀胱癌的围手术期度伐利尤单抗（Durvalumab）联合新辅助化疗
背景
对于适合使用顺铂治疗的肌层浸润性膀胱癌患者，新辅助化疗后进行根治性膀胱切除术是标准治疗方法。添加围手术期免疫疗法可能会改善预后。
方法
在这项3期、开放标签的随机试验中，研究者以1:1的比例将符合顺铂治疗条件的肌层浸润性膀胱癌患者随机分组，一组接受durvalumab新辅助加吉西他滨-顺铂治疗（每3周1次，共4个周期），随后接受根治性膀胱切除术和durvalumab辅助治疗（每4周一次，共8个周期）（durvalumab 组），另一组接受吉西他滨-顺铂新辅助治疗，随后单独接受根治性膀胱切除术（对照组）。两个主要终点之一是无事件生存期。关键的次要终点是总生存期。
结果
总共有533名患者被分配到durvalumab组，530名患者被分配到对照组。durvalumab组估计24个月无事件生存率为67.8%（95% CI，63.6 ~ 71.7），对照组为59.8%（95% CI，55.4 ~ 64.0）（进展、复发、未接受根治性膀胱切除术或全因死亡的风险比为0.68；95% CI，0.56 ~ 0.82；分层对数秩检验P <0.001）。预计24个月总生存率：durvalumab组为82.2%（95% CI，78.7 ~ 85.2），对照组为75.2%（95% CI，71.3 ~ 78.8）（死亡风险比为0.75；95% CI，0.59 ~ 0.93；分层对数秩检验 P=0.01）。durvalumab组40.6%的患者和对照组40.9%的患者发生了严重程度为3级或4级的治疗相关不良事件；两组均有0.6%的患者发生了导致死亡的治疗相关不良事件。durvalumab组88.0%的患者和对照组 83.2%的患者接受了根治性膀胱切除术。
结论
与单纯新辅助化疗相比，围手术期durvalumab联合新辅助化疗可显著改善无事件生存率和总生存率。
4.Transcatheter Valve Repair in Heart Failure with Moderate to Severe Mitral Regurgitation
AFFILIATIONS
From the Department of Cardiology of German Heart Center Charité and the Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin (S.D.A., M.D., W.H.), the Department of Cardiology, Angiology, and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, the Berlin Institute of Health, and DZHK Partner Site Berlin (U.L.), Deutsches Herzzentrum der Charité, the Department of Cardiology, Angiology, and Intensive Care Medicine, Campus Charité Mitte, the Center for Cardiovascular Telemedicine, and DZHK Partner Site Berlin, Charité Universitätsmedizin (F.K.), Berlin, the Departments of Cardiology and Pneumology (S.D.A., M.D., G.H., W.S.) and Medical Statistics (T.F., M.P.) and the Clinical Trial Unit (J.H.), University Medical Center Göttingen, and the Heart Center, Department of Cardiology (W.S.), Georg August University of Göttingen, DZHK Partner Site Göttingen, Göttingen, the Department of Cardiology, University Medical Center of the Johannes Gutenberg–University Mainz (R.S.B., M. Geyer, T.F.R.), Mainz, the Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, and Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf (M. Kelm), the Department of Rhythmology, University Heart Center Lübeck, University Hospital Schleswig–Holstein, Lübeck (K.-H.K.), the West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, University Hospital Essen, University Duisburg–Essen, Essen (T.R.), the Heart and Vascular Center, Bad Bevensen (U.S.), the Department of Internal Medicine I, Cardiology, University Hospital Jena, Jena (P.C.S.), the Institute for Cardiovascular Regeneration, Goethe University Frankfurt, and DZHK Partner Site Rhein–Main, Frankfurt am Main (A.Z.), the Department of Intensive Care Medicine, University Medical Center Hamburg–Eppendorf, and DZHK Partner Site Hamburg–Kiel–Lübeck, Hamburg (M. Karakas), the Department of Cardiology, Rostock University Medical Center, Rostock (A.Ö.), the Department of Medicine, Heart and Vascular Center, Division of Cardiology and Vascular Medicine, Johanniter Hospital Stendal, Stendal (M. Gross), the Mid-German Heart Center, Department of Cardiology, Angiology, and Intensive Care Medicine, University Hospital Halle, Halle (J.T.) — all in Germany; the Department of Medicine, University of Mississippi Medical Center, Jackson (J.B.); Baylor Scott and White Research Institute, Dallas (J.B., M.S.K.), Baylor Scott and White the Heart Hospital Plano, Plano (M.S.K.), and the Department of Medicine, Baylor College of Medicine, Temple (M.S.K.) — all in Texas; the Department of Translational Medicine, University of Ferrara, Ferrara (R.F.), the Cardiac Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan (O.A.), ANMCO Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Heart Care Foundation, Florence (A.P.M.), and the Institute of Cardiology, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, and the Department of Medical and Surgical Specialties, Radiologic Sciences and Public Health, University of Brescia, Brescia (M.M., M.A.) — all in Italy; the Division of Cardiovascular Medicine, Ohio State University, Columbus (W.T.A.); the Department of Cardiology, Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano (A.A.), and the Center for Translational and Experimental Cardiology, Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich (F.R.) — both in Switzerland; the Heart Institute, Hospital Universitari Germans Trias i Pujol, Barcelona (A.B.-G., E.S.-V.), and the Department of Cardiology, Hospital Universitario Ramón y Cajal, and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid (J.L.Z.) — all in Spain; the School of Cardiovascular and Metabolic Health, University of Glasgow, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, United Kingdom (J.G.F.C., M.C.P.); the Department of Cardiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens (G.F.), and the Department of Transcatheter Heart Valves, Hygeia Hospital (K.S., M.C., P.K., K.P.), Athens, and the Department of Cardiology, St. Luke’s Hospital (N.M., E.K.T.), and the European Interbalkan Medical Center (V.N., I.N., K.P.), Thessaloniki — all in Greece; the Department of Cardiology, Copenhagen University Hospital–Rigshospitalet, Copenhagen (F.G.); Unité Formation et Recherche Médecine, Université de Paris-Cité, site Bichat, Laboratoire de Recherche Vasculaire Translationnelle, INSERM, Groupe Hospitalier Bichat, Paris (A.V.); the Division of Cardiology, General Hospital Murska Sobota, Murska Sobota, and the Faculty of Medicine, University of Ljubljana, Ljubljana — both in Slovenia (M.L.); the Division of Cardiology and Structural Heart Diseases (G.S., W.W.) and the Department of Cardiology, Congenital Heart Diseases, and Electrotherapy (Z.K.), Medical University of Silesia, Katowice, the Institute of Heart Diseases, Medical University and University Hospital, Wrocław (K.R., P.P.), and the Department of Interventional Cardiology, Department of Radiology and Diagnostic Imaging, John Paul II Hospital, Krakow (Ł.W.) — all in Poland; and Centro Academico de Medicina de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal (F.J.P.).
Abstract
Background
Whether transcatheter mitral-valve repair improves outcomes in patients with heart failure and functional mitral regurgitation is uncertain.
Methods
We conducted a randomized, controlled trial involving patients with heart failure and moderate to severe functional mitral regurgitation from 30 sites in nine countries. The patients were assigned in a 1:1 ratio to either transcatheter mitral-valve repair and guideline-recommended medical therapy (device group) or medical therapy alone (control group). The three primary end points were the rate of the composite of first or recurrent hospitalization for heart failure or cardiovascular death during 24 months; the rate of first or recurrent hospitalization for heart failure during 24 months; and the change from baseline to 12 months in the score on the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS; scores range from 0 to 100, with higher scores indicating better health status).
Results
A total of 505 patients underwent randomization: 250 were assigned to the device group and 255 to the control group. At 24 months, the rate of first or recurrent hospitalization for heart failure or cardiovascular death was 37.0 events per 100 patient-years in the device group and 58.9 events per 100 patient-years in the control group (rate ratio, 0.64; 95% confidence interval [CI], 0.48 to 0.85; P=0.002). The rate of first or recurrent hospitalization for heart failure was 26.9 events per 100 patient-years in the device group and 46.6 events per 100 patient-years in the control group (rate ratio, 0.59; 95% CI, 0.42 to 0.82; P=0.002). The KCCQ-OS score increased by a mean (±SD) of 21.6±26.9 points in the device group and 8.0±24.5 points in the control group (mean difference, 10.9 points; 95% CI, 6.8 to 15.0; P<0.001). Device-specific safety events occurred in 4 patients (1.6%).
Conclusions
Among patients with heart failure with moderate to severe functional mitral regurgitation who received medical therapy, the addition of transcatheter mitral-valve repair led to a lower rate of first or recurrent hospitalization for heart failure or cardiovascular death and a lower rate of first or recurrent hospitalization for heart failure at 24 months and better health status at 12 months than medical therapy alone.
4.伴中度至重度二尖瓣反流的心力衰竭患者的经导管瓣膜修复术
背景
经导管二尖瓣修复是否能改善心力衰竭合并功能性二尖瓣反流患者的预后尚不确定。
方法
该研究在9个国家的30个研究中心开展了一项随机对照试验，纳入了心力衰竭合并中度至重度功能性二尖瓣反流患者。按1:1的比例将患者随机分配到接受经导管二尖瓣修复术和指南推荐的药物治疗组（器械组）或单纯药物治疗组（对照组）。三个主要终点是24个月内首次或反复因心力衰竭住院或心血管死亡的综合发生率；24个月内首次或反复因心力衰竭住院的发生率；以及从基线到12个月的堪萨斯城心肌病问卷总体总结（KCCQ-OS；分数范围为0 ~ 100，分数越高表示健康状况越好）分数的变化。
结果
共有505名患者接受了随机分组：250名患者被分配至器械组，255名患者被分配至对照组。24个月时，器械组首次或复发心力衰竭住院或心血管原因死亡的发生率为每100患者年37.0起，对照组为每100患者年58.9起（率比为0.64；95% CI，0.48 ~ 0.85；P=0.002）。器械组因心力衰竭首次或复发住院的发生率为每100患者年26.9起，对照组为每100患者年46.6起（率比为 0.59；95% CI，0.42 ~ 0.82；P=0.002）。器械组的KCCQ-OS评分平均（±SD）增加 21.6±26.9分，对照组增加8.0±24.5分（平均差异为10.9分；95% CI，6.8 ~ 15.0；P<0.001）。4名患者（1.6%）发生了器械相关安全事件。
结论
对于接受药物治疗的患有中度至重度功能性二尖瓣反流的心力衰竭患者，联合进行经导管二尖瓣修复术可降低因心力衰竭或心血管死亡而首次或复发住院的发生率，并且与单纯药物治疗相比，可降低24个月时因心力衰竭而首次或复发住院的发生率，以及改善12个月时的健康状况。
5.Preoperative Chemoradiotherapy for Resectable Gastric Cancer
AFFILIATIONS
From the Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne (T.L., M.M., W.K.M.), the School of Public Health, Monash University (J.Z.), the Department of Medical Oncology, Alfred Health (J.Z.), Central Clinical School, Alfred Centre (A.B.), and Monash Medical Centre (A.S.), Melbourne, VIC, Princess Alexandra Hospital, University of Queensland, Brisbane (B.M.S.), and Cancer Care Services, Sunshine Coast University Hospital, Birtinya, QLD (D.W.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney (V.G., R.L.O., J.S.), and Chris O’Brien Lifehouse (D.M.), Sydney, and the Trans-Tasman Radiation Oncology Group, University of Newcastle, Newcastle, NSW (A.M.) — all in Australia; the Department of Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium (K.H.); Princess Margaret Hospital (R.W.) and Mount Sinai Hospital (C.S.), Toronto, the Canadian Cancer Trials Group, Queen’s University, Kingston, ON (C.O.), Nova Scotia Health Central Zone, Halifax (G.D.), and Centre Hospitalier de l’Université de Montréal, Montreal (M.L.) — all in Canada; the Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (M.F.); University Cancer Center Leipzig and Comprehensive Cancer Center Central Germany Leipzig–Jena, University Medicine Leipzig, Leipzig, Germany (F.L.); and Sainte Catherine Institut du Cancer Avignon–Provence, Avignon, France (L.M.).
Abstract
Background
In Western countries, the current standard of care for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy has been considered, but data are limited regarding this treatment as compared with perioperative chemotherapy alone.
Methods
We conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life.
Results
A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups.
Conclusions
The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve overall survival as compared with perioperative chemotherapy alone among patients with resectable gastric and gastroesophageal junction adenocarcinoma.
5.可切除胃癌的术前放化疗
背景
在西方国家，目前可切除胃癌的标准治疗是围手术期化疗。术前放化疗也曾被考虑，但与单纯围手术期化疗相比，关于该治疗的数据有限。
方法
该研究开展了一项国际性3期试验，将可切除的胃或胃食管交界处腺癌患者随机分组，分别接受术前放化疗加围手术期化疗或单纯围手术期化疗（对照组）。两组患者在手术前后均接受表柔比星、顺铂和氟尿嘧啶或氟尿嘧啶、亚叶酸钙、奥沙利铂和多西他赛治疗；术前放化疗组还接受了放化疗（45Gy分25次放射治疗，加氟尿嘧啶输注）。主要终点是总生存期，次要终点包括无进展生存期、病理完全缓解、毒性作用和生活质量。
结果
该研究共纳入了来自澳大利亚、加拿大和欧洲的 70 个研究中心的574名患者，并进行随机分组：术前放化疗组286名，围手术期化疗组288名。术前放化疗组患者的病理完全缓解率（17% vs. 8%）和术后肿瘤降期程度均高于围手术期化疗组。中位随访期67个月时，两组间总生存期与无进展生存期均无显著差异。术前放化疗组患者中位总生存期为46个月，围手术期化疗组患者中位总生存期为49个月（死亡风险比为1.05；95% CI，0.83 ~ 1.31），中位无进展生存期分别为31个月和32个月。两组的治疗相关毒性作用相似。
结论
对于可切除的胃腺癌和胃食管连接部腺癌患者，相比仅进行围手术期化疗而言，在围手术期化疗基础上联合术前放化疗相较于单纯围手术期化疗，未能显著提高总生存期。
November 21, 2024; Volume 391 (20): 1865-1968
在2024年11月21日，共发表18篇文章，其中包括4篇Perspective，4篇Original articles，1篇Review Article，2篇Images in clinical medicine，1篇Case Records of the Massachusetts General Hospital，1篇Editorial，1篇Special Report，4篇Correspondence。
6.Adjunctive Middle Meningeal Artery Embolization for Subdural Hematoma
AFFILIATIONS
From the Departments of Neurosurgery (J.M.D., A.H.S.), Biomedical Informatics (J.M.D.), and Radiology (A.H.S.), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, the Department of Neurological Surgery, New York Presbyterian Hospital–Weill Cornell Medical Center (J.K.), and the Department of Neurosurgery, Icahn School of Medicine at Mount Sinai (C.P.K.), New York, the Department of Neurosurgery, North Shore University Hospital at Northwell Health, Great Neck (T.W.L.), the Department of Neurosurgery, Albany Medical Center, Albany (A.R.P.), and the Department of Neurosurgery, Westchester Medical Center at New York Medical College, Valhalla (J. Santarelli) — all in New York; the Department of Neurosurgery and Brain Repair, University of South Florida, and Tampa General Hospital, Tampa (M.M.), Lyerly Neurosurgery, Baptist Medical Center Jacksonville, Jacksonville (R.A.H.), the Orlando Health Neuroscience Institute, Division of Neurosurgery, Orlando Health, Orlando Regional Medical Center, Orlando (M.C.C.), and the Department of Neurosurgery, University of Florida, Gainesville (M.J.K.) — all in Florida; the Department of Neuroscience, Valley Baptist Medical Center, and the Department of Neurology, University of Texas Rio Grande Valley, Harlingen (A.E.H.), the Department of Neurosurgery, Memorial Hermann–Texas Medical Center, Houston (P.R.C.), and the Department of Neurosurgery, Baylor Scott and White Health, Temple (W.S.L.) — all in Texas; the Departments of Neurosurgery and Engineering Science and Mechanics, Penn State University, Hershey (R.E.H.), the Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh (B.A.G.), and the Department of Neurosurgery, Geisinger and Geisinger Commonwealth School of Medicine, Wilkes-Barre (C.M.S.) — all in Pennsylvania; the Departments of Neurological Surgery, Surgery, Radiology, and Neurosciences, University of California, San Diego, La Jolla (A.K.), the Departments of Radiology (J.T.) and Neurosurgery (W.S.), Providence Little Company of Mary Medical Center, Torrance, Pacific Neuroscience Institute, Santa Monica (J.T., W.S.), and the Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles (W.J.M.) — all in California; the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg–Eppendorf, Hamburg, Germany (J.F.); the Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City (R.G.); the Cerebrovascular Center, Cleveland Clinic, Cleveland (M.B.), the Department of Neurology, ProMedica Toledo Hospital–University of Toledo College of Medicine and Life Sciences, Toledo (M.J.), and Wexner Medical Center, Ohio State University, Columbus (P.Y.) — all in Ohio; the Department of Neurosurgery, Rush University, Chicago (R.W.C.), and the Department of Neurosciences, Advocate Lutheran General Hospital, Park Ridge (J.B.) — both in Illinois; the Departments of Neurological Surgery, Neurology, Radiology, Otolaryngology, and Neuroscience, University of Kentucky, Lexington (J.F.F.); the Departments of Neurological Surgery, Radiology, Neurology, and Mechanical Engineering and the Stroke and Applied Neuroscience Center, University of Washington, Seattle (M.R.L.); the Department of Neurosurgery, Atrium Health Carolinas Medical Center, and Carolina Neurosurgery and Spine Associates — both in Charlotte, NC (J.D.B.); the Department of Diagnostic Radiology and Neuroradiology, Prisma Health Southeastern Neurosurgical and Spine Institute, Greenville, SC (M.I.C.); the Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City (H.J.S.); the Departments of Neurosurgery and Radiology, University of Alabama School of Medicine, Birmingham (J.J.); the Departments of Neurosurgery, Radiology, and Neurology, Washington University in St. Louis, St. Louis (J.W.O.); the Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City (K.D.); the Department of Neurosurgery, Emory University School of Medicine, Atlanta (J.A.G.); the Department of Neurointerventional Radiology, Goodman Campbell Brain and Spine, Indianapolis (D.H.S.); the Department of Neurosurgery, Michigan State University College of Human Medicine, Grand Rapids (J.S.), the Department of Neurology, McLaren Flint Hospital, Flint (A.Q.M.), and McLaren Macomb Hospital, Mount Clemens (A.Q.M.) — all in Michigan; the Department of Neurological Surgery, Oregon Health and Science University, Portland (J.J.L.); Aurora Neuroscience Innovation Institute, Milwaukee (T.W.); the Division of Neurointerventional Radiology, Department of Radiology, Beth Israel Lahey Health, Lahey Hospital and Medical Center, Burlington, MA (N.V.P.); and the Department of Neurosurgery, University of Colorado, Denver (C.R.).
Abstract
Background
Subacute and chronic subdural hematomas are common and frequently recur after surgical evacuation. The effect of adjunctive middle meningeal artery embolization on the risk of reoperation remains unclear.
Methods
In a prospective, multicenter, interventional, adaptive-design trial, we randomly assigned patients with symptomatic subacute or chronic subdural hematoma with an indication for surgical evacuation to undergo middle meningeal artery embolization plus surgery (treatment group) or surgery alone (control group). The primary end point was hematoma recurrence or progression that led to repeat surgery within 90 days after the index treatment. The clinical secondary end point was deterioration of neurologic function at 90 days, which was assessed with the modified Rankin scale in a noninferiority analysis (margin for risk difference, 15 percentage points).
Results
A total of 197 patients were randomly assigned to the treatment group and 203 to the control group. Surgery occurred before randomization in 136 of 400 patients (34.0%). Hematoma recurrence or progression leading to repeat surgery occurred in 8 patients (4.1%) in the treatment group, as compared with 23 patients (11.3%) in the control group (relative risk, 0.36; 95% confidence interval [CI], 0.11 to 0.80; P=0.008). Functional deterioration occurred in 11.9% of the patients in the treatment group and in 9.8% of those in the control group (risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the treatment group and 3.0% in the control group. By 30 days, serious adverse events related to the embolization procedure had occurred in 4 patients (2.0%) in the treatment group, including disabling stroke in 2 patients; no additional events had occurred by 180 days.
Conclusions
Among patients with symptomatic subacute or chronic subdural hematoma with an indication for surgical evacuation, middle meningeal artery embolization plus surgery was associated with a lower risk of hematoma recurrence or progression leading to reoperation than surgery alone. Further study is needed to evaluate the safety of middle meningeal artery embolization in the management of subdural hematoma.
6.辅助性脑膜中动脉栓塞术治疗硬膜下血肿
背景
亚急性和慢性硬膜下血肿很常见，且手术清除后经常复发。辅助性脑膜中动脉栓塞术对降低再次手术风险的影响尚不清楚。
方法
该研究为一项前瞻性、多中心、干预性、适应性设计临床试验，纳入且有手术清除指征的有症状的亚急性或慢性硬膜下血肿患者，随机分配至接受脑膜中动脉栓塞联合手术组（治疗组）或单纯手术组（对照组）。主要终点是初始治疗后90天内因血肿复发或进展需行再次手术。次要临床终点是90天时的神经功能恶化，通过改良的Rankin量表进行非劣效性分析（风险差异边界为15个百分点）。
结果
共有 197 名患者被随机分配至治疗组，203名患者被分配至对照组。400名患者中，有136名（34.0%）在随机分组前进行了手术。治疗组有8例（4.1%）患者因血肿复发或进展而需再次手术，而对照组有23例（11.3%）患者（相对风险 0.36；95% CI，0.11 ~ 0.80；P=0.008）。治疗组有11.9%的患者出现功能恶化，对照组有9.8%的患者出现功能恶化（风险差异 2.1个百分点；95% CI -4.8 ~ 8.9）。治疗组90天死亡率为5.1%，对照组为3.0%。到30天时，治疗组有4例（2.0%）患者发生了与栓塞手术相关的严重不良事件，包括2例致残性卒中；到180天时未发生其他事件。
结论
对于需要手术清除的有症状的亚急性或慢性硬膜下血肿患者，脑膜中动脉栓塞术加手术与单纯手术相比，血肿复发或进展导致再次手术的风险较低。需要进一步研究来评估脑膜中动脉栓塞术在硬膜下血肿治疗中的安全性。
7.Middle Meningeal Artery Embolization for Nonacute Subdural Hematoma
AFFLIATIONS
From the Neurovascular Center (J. Liu, Q.Z., P.Z., L.C., Yongxin Zhang, F.S., Y. Wu, G.D., N.L., X.X., Zifu Li, Y. Zhou, L.Z., D.D., Yongwei Zhang, R.Z., Y.X., Q.L., P.Y.), Trauma Center (J. Liu, Q.Z.), and Department of Radiology (B.T.), Naval Medical University Changhai Hospital, the Key Laboratory of Molecular Neurobiology of the Ministry of Education, Naval Medical University (J. Liu, P.Y.), the Oriental PanVascular Devices Innovations College, University of Shanghai for Science and Technology (J. Liu, H.Z., P.Y.), the Departments of Neurosurgery (W.N., H.Y., J.Y., Z.D., J.H., Q.Y., G.W., C.G., X.W., H.J., J.S., Y.G., Y.M.) and Neurology (X.C., Z.W.), and the National Center for Neurological Disorders (Y.G., Y.M.), Fudan University Huashan Hospital, the Department of Neurosurgery, Fudan University Huashan Hospital North (Y. Lei, Yanjiang Li, L.X.), Neurosurgical Institute Fudan University and Shanghai Clinical Medical Center of Neurosurgery (Y.G., Y.M.), the Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (X.H.), the Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University (J. Wan), the Department of Neurosurgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Yi Li), and the Department of Neurosurgery, Shanghai Tenth People’s Hospital (L.G.), Shanghai, the Department of Neurosurgery, First People’s Hospital of Changzhou, Changzhou (Y.P.), the Department of Neurosurgery, First Affiliated Hospital of Ningbo University, Ningbo (Z. Lin), the Department of Neurosurgery, Yijishan Hospital, the First Affiliated Hospital of Wannan Medical College, Wuhu (Zhenbao Li), the Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng (J. Wang), the Department of Neurosurgery, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou (Y. Zhen), the Department of Neurosurgery, First Affiliated Hospital of Anhui Medical University, Hefei (J. Luo), the Department of Neurosurgery, First Affiliated Hospital of Fujian Medical University, Fuzhou (Y. Lin), the Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong (J.C.), the Department of Neurosurgery, Jiangsu Provincial Hospital, the First Affiliated Hospital of Nanjing Medical University, Nanjing (H.L.), the Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou (M.Z.), the Department of Neurosurgery, Shantou Central Hospital, Shantou (M.L.), the Department of Neurosurgery, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou (J.Z.), the Department of Neurosurgery, Capital Medical University Beijing Chaoyang Hospital, Beijing (Y. Wang), the Department of Neurosurgery, Henan Provincial People’s Hospital, Zhengzhou (T.L.), the Department of Neurosurgery, Second Affiliated Hospital of Nanchang University, Nanchang (G.M.), the Department of Neurosurgery, Zhongnan Hospital Wuhan University, Wuhan (W.Z.), the Department of Neurosurgery, the First Hospital of Hebei Medical University, Shijiazhuang (C.L.), and the Department of Neurosurgery, Zhongshan Hospital Xiamen University, Xiamen (E.C.) — all in China; the Departments of Diagnostic Imaging (J.M.O.), Radiology (M.G.), and Clinical Neurosciences (M.G.), University of Calgary, Calgary, AB, Canada; and the Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam (C.B.L.M.M.).
Abstract
Background
The effect of embolization of the middle meningeal artery in patients with subacute or chronic subdural hematoma is uncertain.
Methods
We performed a multicenter, open-label, randomized trial in China, involving patients with symptomatic nonacute subdural hematoma with mass effect. Patients were assigned to undergo burr-hole drainage or receive nonsurgical treatment at the surgeon’s discretion, and patients in each group were then randomly assigned, in a 1:1 ratio, to undergo middle meningeal artery embolization with liquid embolic material or to receive usual care. Patients whose condition warranted craniotomy were excluded. The primary outcome was symptomatic recurrence or progression of subdural hematoma within 90 days after randomization. Secondary outcomes included clinical and imaging outcomes. The main safety outcome was any serious adverse event (including death).
Results
The analysis included 722 patients, of whom 360 were assigned to the embolization group and 362 to the usual-care group. Burr-hole drainage was performed in 78.3% of the enrolled patients; among the patients who underwent burr-hole drainage, the procedure occurred after embolization in 99.6%. Symptomatic recurrence or progression of subdural hematoma within 90 days occurred in 24 patients (6.7%) in the embolization group and in 36 (9.9%) in the usual-care group (between-group difference, −3.3 percentage points; 95% confidence interval, −7.4 to 0.8; P=0.10). The incidence of serious adverse events was lower in the embolization group than in the usual-care group (6.7% vs. 11.6%, P=0.02).
Conclusions
Among patients with symptomatic nonacute subdural hematoma (of whom 78% underwent burr-hole drainage), middle meningeal artery embolization resulted in a 90-day incidence of symptomatic recurrence or progression similar to that with usual care but was associated with a lower incidence of serious adverse events.
7.脑膜中动脉栓塞治疗非急性硬膜下血肿
背景
对于亚急性或慢性硬膜下血肿患者，脑膜中动脉栓塞的效果尚不明确。
方法
该研究在中国开展了一项多中心、开放标签的随机试验，研究对象为有症状的非急性硬膜下血肿且伴有占位效应的患者。患者被分配接受钻孔引流或接受非手术治疗（由外科医生酌情决定），然后每组患者按1:1的比例随机分配接受液体栓塞材料进行脑膜中动脉栓塞术或接受常规治疗。排除病情需要开颅手术的患者。主要结局是随机分组后90天内硬膜下血肿的症状复发或进展。次要结局包括临床和影像学结局。主要安全性结局是严重不良事件（包括死亡）。
结果
共纳入了722例患者，其中360例被分配至栓塞组，362例被分配至常规治疗组。78.3%的患者接受了钻孔引流术，其中99.6%的患者在栓塞术后实施钻孔引流。栓塞组有24例患者（6.7%）和常规治疗组有36例患者（9.9%）在90天内出现有症状的硬膜下血肿复发或进展（组间差异为-3.3 个百分点；95% CI,-7.4 ~ 0.8；P=0.10）。栓塞组的严重不良事件发生率显著低于常规治疗组（6.7% vs. 11.6%，P=0.02）。
结论
对于有症状的非急性硬膜下血肿患者（其中78%接受了钻孔引流），脑膜中动脉栓塞治疗导致的90天内症状性复发或进展发生率与常规治疗相似，但严重不良事件发生率更低。
8.Nationwide, Couple-Based Genetic Carrier Screening
Affiliations
From the Centre for Clinical Genetics, Sydney Children’s Hospital (E.P.K., K.B., S.R., S.K.), NSW Health Pathology Randwick Genomics Laboratory (E.P.K., B.R., C.C.C., F.Z., J.F., M.B., N.Q., S.R., S.K., T.R., Y.Z.), the School of Clinical Medicine (E.P.K., M.B.), the School of Women’s and Children’s Health (L. Freeman, S.R., S.K.), and the Randwick Clinical Campus, Neuroscience Research Australia (Y.Z.), University of New South Wales, Randwick, Victorian Clinical Genetics Services (M.B.D., A.D.A., A.K.-P., C.H., C.L., I.D., J.E.M., K.S., L.G., L.T., M.C.O., M. Wall, M.T.M.C., M.M.F., N.L., S. Lunke, S. Eggers), the Bruce Lefroy Centre, Murdoch Children’s Research Institute (M.B.D., E.A.K.), the Department of Paediatrics (M.B.D., A.D.A., E.T., J.L.H., S. Lewis, B.J.M., J. Massie, E.A.K., Z.F.), the Department of General Practice and Centre for Cancer Research (J.D.E.), and the Department of Pathology (Sebastian Lunke), University of Melbourne, Murdoch Children’s Research Institute (A.D.A., E.T., J.C., J.L.H., S. Lewis, B.J.M., J. Massie, A.R., E.A.K., E.O.M., L.G., M.H., S.J., S. Lunke, S. Eggers, T.F.B.), and Australian Genomics (J.C., A.J.N., S.B., Jeffrey Braithwaite, E.O.M., K.B., S.J., Z.F., T.F.B.), Parkville, VIC, the Faculty of Medicine and Health, Sydney School of Public Health, Sydney Health Ethics, University of Sydney, Camperdown, NSW (A.J.N., L.D.), the Graduate School of Health, University of Technology Sydney (L.D., L. Freeman), Macquarie University, Australian Institute of Health Innovation (J.C.L., J. Braithwaite, T.T.), and the Faculty of Medicine and Health, University of New South Wales (K.B.-S.), Sydney (R.C.), the Peter MacCallum Cancer Centre (S.B.), the Victorian Comprehensive Cancer Centre (S.B.), the Sir Peter MacCallum Department of Oncology (S.B.) and the Department of Obstetrics and Gynaecology (S.P.W.), University of Melbourne, the Department of Respiratory Medicine and Children’s Bioethics Centre, the Royal Children’s Hospital (J. Massie), Genomic Diagnostics (A.K.), and Virtus Health, Virtus Genetics (S.S.-M.), Melbourne, VIC, Menzies Health Institute Queensland, Griffith University, and Griffith University School of Medicine and Dentistry, Gold Coast (M.J.D., P.A.S.), the Northern Clinical School, Faculty of Medicine and Health (K.B.S., L.B.), and Royal North Shore Hospital, Kolling Institute, Cancer Genetics Laboratory (Y.Z.), University of Sydney, St. Leonards, NSW, SA Pathology (A.K., T.H.), South Australian Clinical Genetics Service (J.L.) and the Pediatric and Reproductive Genetics Unit (L. Fitzgerald), Women’s and Children’s Hospital, and Repromed (J.L.), Adelaide, the Children’s Hospital at Westmead, Sydney Genome Diagnostics (B.H.B., G.H., K.F.), the Specialty of Genomic Medicine, Faculty of Medicine and Health, the Children’s Hospital at Westmead Clinical School, University of Sydney (B.H.B., G.H., K.F.), and the Department of Clinical Genetics, the Children’s Hospital at Westmead (K.B.), Westmead, NSW, Genetic Health Queensland, Royal Brisbane and Women’s Hospital (C.E., J. McGaughran, T. Clinch), and the School of Medicine, University of Queensland (Julie McGaughran), Brisbane, the Department of Diagnostic Genomics, PathWest Laboratory Medicine (D.A., M.R.D., P.K.P., R.J.N.A., R.O., T. Catchpool, N.G.L.), the School of Biological Sciences, Centre for Genetic Origins of Health and Disease (J. Beilby), the Centre for Medical Research (M.R.D., R.O., N.G.L.), and the Faculty of Health and Medical Sciences (N.P.), University of Western Australia, and Harry Perkins Institute of Medical Research (R.O., Samantha Edwards, N.G.L.), Nedlands, the Department of Pathology and Laboratory Medicine, Medical School, University of Western Australia (D.A.), and Genetic Services of Western Australia, King Edward Memorial Hospital (J.K., N.P.), Perth, the Tasmanian Clinical Genetics Service (K.H., M. Wallis) and the School of Medicine and Menzies Institute for Medical Research (M. Wallis), University of Tasmania, Hobart, the Garvan Institute of Medical Research and the School of Clinical Medicine, St. Vincent’s Clinical Campus, University of New South Wales, Darlinghurst (L.B.), King Edward Memorial Hospital, Subiaco, WA (N.P.), the School of Biomedical Sciences, University of Western Australia, Crawley (R.J.N.A.), Sonic Healthcare, Douglass Hanly Moir Pathology, Macquarie Park, NSW (S.S.), Mercy Hospital for Women, Mercy Perinatal, Heidelberg, VIC (S.P.W.), and Monash IVF Group, Richmond, VIC (T.H.) — all in Australia; and the International Society for Quality in Health Care, Dublin (J. Braithwaite).
Abstract
Background
Genomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition.
Methods
We investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie’s Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy. The results obtained from testing at least 1281 genes were provided to the reproductive couples. We aimed to ascertain the psychosocial effects on participants, the acceptability of screening to all participants, and the reproductive choices of persons identified as having an increased chance of having a child with a condition for which we screened.
Results
Among 10,038 reproductive couples enrolled in the study, 9107 (90.7%) completed screening, and 175 (1.9%) were newly identified as having an increased chance of having a child with a genetic condition for which we screened. These conditions involved pathogenic variants in 90 different genes; 74.3% of the conditions were autosomal recessive. Three months after receiving the results, 76.6% of the couples with a newly identified increased chance had used or planned to use reproductive interventions to avoid having an affected child. Those newly identified as having an increased chance had greater anxiety than those with a low chance. The median level of decisional regret was low in all result groups, and 98.9% of participants perceived screening to be acceptable.
Conclusions
Couple-based reproductive genetic carrier screening was largely acceptable to participants and was used to inform reproductive decision making. The delivery of screening to a diverse and geographically dispersed population was feasible.
8.全国范围内以夫妇为基础的遗传携带者筛查
背景
与一般人群相比，基因组测序技术可以识别出更有可能生出患有常染色体隐性或X连锁遗传病的孩子的生育夫妇。
方法
作为麦肯齐使命项目的一部分，该研究调查了澳大利亚全国范围内以夫妇为基础的遗传携带者筛查计划的可行性、可接受性和结果。医疗保健提供者向育龄夫妇在孕前或孕早期提供筛查服务，检测涵盖至少1281个基因的变异信息。旨在确定筛查对参与者的心理社会影响、所有参与者对筛查的可接受性，以及高风险夫妇的生育选择。
结果
在该研究招募的10,038对育龄夫妇中，9107对（90.7%）完成了筛查，175 对（1.9%）被新发现生下患有筛查的遗传疾病的孩子的可能性增加。这些疾病涉及90种不同基因的致病变异；74.3%的疾病是常染色体隐性遗传。在收到结果三个月后，76.6%的新发现可能性增加的夫妇已经使用或计划使用生殖干预措施来避免生下患病的孩子。那些新发现可能性增加的人比可能性较低的人更焦虑。所有结果组的决策后悔程度中位数都很低，98.9%的参与者认为筛查是可以接受的。
结论
以夫妻为基础的生殖遗传携带者筛查在很大程度上为参与者所接受，并被用于指导生育决策。该筛查模式在人口结构多样化且地理分布广泛的人群中具有实施可行性。
November 28, 2024；Volume 391 (21)：1969-2064
在2024年11月28日，共发表23篇文章，其中包括5篇Perspective，4篇Original articles，1篇Clinical Practice, 2篇Images in Clinical Medicine，1篇Case Records of the Massachusetts General Hospital，3篇Editorials，1篇Clinical Implications of Basic Research，5篇Correspondence，1篇Correction。
9.Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer
AFFILIATIONS
From the Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London (P.S.); International Breast Cancer Center, Pangaea Oncology, Quirónsalud Group, and Medical Scientia Innovation Research, Barcelona, and IOB Madrid, Institute of Oncology, Hospital Beata María Ana, and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid — all in Spain (J.C.); National Cancer Center Singapore, Duke–National University of Singapore Medical School, Singapore (R.D.); University of Texas Southwestern Medical Center (H.M.) and Baylor University Medical Center, Texas Oncology, Sarah Cannon Research Institute (J.O.) — both in Dallas; Yale School of Medicine, Yale Cancer Center, New Haven, CT (L.P.); the Breast Unit, Department of Gynecology with Breast Center, Kliniken Essen-Mitte, Essen (S.K.), Charité–Universitätsmedizin Berlin (S.K.) and the Breast Cancer Center, Helios Klinikum Berlin–Buch (M.U.), Berlin, the Institute of Pathology, Philipps University of Marburg and University Hospital Marburg, Marburg (C.D.), the Breast Center, Department of Obstetrics and Gynecology and Comprehensive Cancer Center Munich, LMU University Hospital, Munich (N.H.), and University Hospital Erlangen, Comprehensive Cancer Center Erlangen–European Metropolitan Region of Nuremberg, Erlangen (P.A.F.) — all in Germany; Samsung Medical Center, Sungkyunkwan University School of Medicine (Y.H.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University (S.-A.I.) — both in Seoul, South Korea; Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney, Sydney (R.H.); the Center of Cancer Medicine, School of Clinical Medicine, University of Hong Kong, Hong Kong (R.H.); Hokkaido University Hospital, Sapporo, Japan (M.T.); Centre Jean-Perrin, Clermont-Ferrand, France (M.-A.M.-R.); the Department of Oncology–Pathology, Karolinska Institutet, and Breast Center, Theme Cancer, Karolinska University Hospital, Stockholm (T.F.); Instituto Português de Oncologia do Porto Francisco Gentil, Porto (M.F.), and the Breast Unit, Champalimaud Clinical Center–Champalimaud Foundation, Lisbon (F.C.) — both in Portugal; and the Department of Oncology, Merck, Rahway, NJ (X.Z., V.K., K.T., G.A.).
Abstract
Background
In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival.
Methods
We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin–cyclophosphamide or epirubicin–cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab–chemotherapy group) or placebo (placebo–chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point.
Results
Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab–chemotherapy group and 390 to the placebo–chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab–chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo–chemotherapy group (P=0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy.
Conclusions
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer.
9. 帕博利珠单抗治疗早期三阴性乳腺癌的总体生存率
背景
对于早期三阴性乳腺癌患者，Ⅲ期KEYNOTE-522试验表明，在含铂化疗基础上添加帕博利珠单抗可显著改善病理完全缓解率和无事件生存期。该研究在此报告了总生存期的最终分析结果。
方法
该研究将初治的II期或III期三阴性乳腺癌患者以2:1的比例随机分配至两组：试验组接受帕博利珠单抗（200 mg/次）联合紫杉醇+卡铂新辅助治疗（每3周一次，共4周期），后续序贯帕博利珠单抗联合多柔比星-环磷酰胺或表柔比星-环磷酰胺（4周期）；对照组则采用安慰剂替代帕博利珠单抗。术后患者分别接受帕博利珠单抗（试验组）或安慰剂（对照组）辅助治疗（每3周一次，最多9周期）。主要终点是病理完全缓解和无事件生存期。总生存期是次要终点。
结果
在接受随机分组的1174名患者中，784名被分配至帕博利珠单抗联合化疗组，390名被分配至安慰剂联合化疗组。截至数据截止日期（2024 年3月22日），中位随访时间为75.1个月（范围：65.9 ~ 84.0）。帕博利珠单抗联合化疗组的 60个月估计总生存率为86.6%（95% CI，84.0 ~ 88.8），而安慰剂联合化疗组为 81.7%（95% CI，77.5 ~ 85.2）（P=0.002）。不良事件与帕博利珠单抗和化疗的已知安全性一致。
结论
与单纯新辅助化疗相比，帕博利珠单抗联合新辅助化疗，序贯辅助帕博利珠单抗治疗可显著改善其早期三阴性乳腺癌患者的总生存期。
10.Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer
AFFILIATION
From Sorbonne Université, Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris, Unité Mixte de Recherche Scientifique 938, and SIRIC CURAMUS, Paris (T.A.), Hopital Foch, Suresnes (J.B.), and Institut Paoli-Calmettes (C.F.), and La Timone, Aix Marseille Université (L.D.), Marseille — all in France; Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona (E.E.), Hospital Universitario Virgen del Rocío, Seville (M.L.L.), Institut Català d’Oncologia, Hospital Universitario Germans Trias i Pujol, Badalona (J.L.M.M.), and Hospital Universitario 12 de Octubre, Imas12, Medicine Department–UCM, Madrid (R.G.-C.) — all in Spain; University Hospitals Gasthuisberg and University of Leuven (KU Leuven), Leuven, Belgium (E.V.C.); the University Hospital of Southern Denmark, Vejle Hospital, Vejle (L.H.J.); Hospital Universitario Fundacion Favaloro, Buenos Aires (G.M.); Centrul de Oncologie Sf Nectarie, Craiova, Romania (M.S.); the National Cancer Center Hospital East, Chiba, Japan (T.Y.); Shanghai East Hospital, Shanghai, China (J.L.); the University of Southern California Norris Comprehensive Cancer Center, Los Angeles (H.-J.L.); Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome (G.T.), and Veneto Institute of Oncology IOV-IRCCS, Padua (S.L.) — both in Italy; the Netherlands Cancer Institute, Amsterdam (M.C.); Cancer Research SA, Adelaide, SA, Australia (R.J.); Hematology-Oncology Practice Eppendorf (HOPE) and University Cancer Center Hamburg (UCCH), Hamburg, Germany (E.G.); the Institute of Cancer of São Paulo, São Paulo (M.I.B.); Adana City Education and Research Hospital, Adana, Turkey (T. Cil); and Bristol Myers Squibb, Princeton, NJ (E.C., T. Chen, M.L., M.D., S.A.)
Abstract
Background
Patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer.
Methods
In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed.
Results
A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group.
Conclusions
Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer.
10.纳武单抗联合伊匹单抗治疗微卫星高度不稳定转移性结直肠癌
背景
微卫星高度不稳定(MSI-H)或错配修复缺陷(dMMR)转移性结直肠癌的患者接受标准化疗（无论是否联合靶向治疗）的预后均不佳。在针对MSI-H或dMMR转移性结直肠癌开展的非随机研究中，纳武利尤单抗（Nivolumab）联合伊匹单抗 （ipilimumab）显示出临床益处。
方法
在这项 3期开放标签试验中，研究者根据当地检测结果，将处于MSI-H或dMMR状态的不可切除或转移性结直肠癌的患者随机分组，分别按2:2:1 的比例接受纳武单抗联合伊匹单抗治疗、单用纳武单抗、化疗联合或不联合靶向治疗。在集中确认MSI-H或dMMR状态的患者中评估了两个主要终点，即无论患者之前是否接受过转移性疾病的全身治疗，与化疗相比，纳武单抗联合伊匹单抗作为一线治疗的无进展生存期，以及与单用纳武单抗相比，纳武单抗联合伊匹单抗治疗的无进展生存期。在这项预设的中期分析中，研究者们评估了第一个主要终点（涉及纳武单抗联合伊匹单抗vs.化疗）。
结果
总共有303名未接受过转移性疾病全身治疗的患者被随机分配接受纳武单抗联合伊匹单抗或化疗治疗；255名患者已确认患有MSI-H或dMMR肿瘤。中位随访时间为31.5个月（范围，6.1 ~ 48.4），纳武单抗联合伊匹单抗治疗组的无进展生存期（主要分析）显著优于化疗组（使用双侧分层对数秩检验计算的组间无进展生存期差异P<0.001）；纳武单抗联合伊匹单抗治疗组的 24个月无进展生存率为72%（95% CI，64 ~ 79），而化疗组为14%（95% CI，6 ~ 25）。24个月时，纳武单抗联合伊匹单抗治疗组的限制平均生存期比化疗组长10.6个月（95% CI，8.4 ~ 12.9），这一结果与无进展生存期的主要分析结果一致。纳武单抗联合伊匹单抗组有23%的患者而化疗组有48%的患者，发生了3级或4级治疗相关不良事件。
结论
对于未接受过MSI-H或dMMR转移性结直肠癌全身治疗的患者，使用纳武单抗联合伊匹单抗治疗的无进展生存期比使用化疗的无进展生存期更长。
December 5, 2024；Volume 391 (22)：2065-2176
在2024年12月5日，共发表23篇文章，其中包括4篇Perspective，5篇Original articles，1篇Review Article, 2篇Images in Clinical Medicine，1篇Case Records of the Massachusetts General Hospital，7篇Editorials，1篇Clinical Implications of Basic Research，2篇Correspondence。
11.Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease
AFFILIATIONS
From the Department of Cardiology (M.S.C., D.-Y.K., J.-M.A., S.-J.P., D.-W.P., G.-B.N.) and the Division of Biostatics (S.-C.Y.), Asan Medical Center, University of Ulsan College of Medicine, the Department of Cardiology, Seoul St. Mary’s Hospital, College of Medicine, Catholic University of Korea (Y.-S.O.), the Department of Cardiology, Veterans Health Service Medical Center (C.H.L.), the Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital (E.-K.C.), the Division of Cardiology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine (C.H.K.), the Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine (K.-M.P.), the Department of Cardiology, Kyung Hee University Hospital at Gangdong, Kyung Hee University Medical College (E.-S.J.), and the Division of Cardiology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, Catholic University of Korea (O.K.), Seoul, the Cardiovascular Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam (J.H.L.), the Department of Cardiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan (G.-M.P.), the Department of Cardiology, Soon Chun Hyang University Hospital Bucheon, Bucheon (H.O.C.), the Department of Cardiology, Hallym University Medical Center, Anyang (K.-H.P.), the Department of Cardiology, Keimyung University Dongsan Hospital, Daegu (J.H.), the Department of Cardiology, St. Vincent’s Hospital, College of Medicine, Catholic University of Korea, Suwon (K.-D.Y.), the Department of Cardiology, Dong-A University Hospital, Dong-A University College of Medicine (Y.-R.C.), and the Department of Cardiology, Haeundae Paik Hospital, Inje University College of Medicine (K.-H.K.), Busan, the Department of Cardiology, Dongguk University Ilsan Hospital, Goyang (J.H.K.), and the Department of Cardiology, Pusan National University Yangsan Hospital, Pusan National University of Medicine, Yangsan (K.W.H.) — all in South Korea.
Abstract
Background
Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking.
Methods
We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA2DS2-VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding.
Results
We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA2DS2-VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan–Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan–Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53).
Conclusions
In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy.
11.依度沙班抗血栓治疗房颤和稳定型冠状动脉疾病
背景
尽管临床指南有一致的建议，但目前仍缺乏关于房颤和稳定型冠状动脉疾病患者的长期抗血栓治疗策略的随机试验数据。
方法
该研究开展了一项多中心、开放标签、裁定者设盲的随机试验，比较了依度沙班单药治疗与双联抗血栓治疗（艾多沙班加一种抗血小板药物）在心房颤动和稳定型冠状动脉疾病（定义为既往接受过血运重建治疗或药物治疗的冠状动脉疾病）患者中的效果。根据CHA2DS2-VASc评分评估卒中风险（评分范围为0 ~ 9，评分较高表示卒中风险较高）。主要结局是12个月时全因死亡、心肌梗死、卒中、全身性栓塞、计划外的紧急血运重建以及大出血或临床相关的非大出血构成的复合结局。次要结局包括重大缺血事件构成的复合结局以及由大出血或临床相关的非大出血构成的安全性结局。
结果
研究者们在韩国的18个研究中心将524名患者分配至依度沙班单药治疗组，将516名患者分配至双联抗血栓治疗组。患者平均年龄为72.1岁，22.9%为女性，平均CHA2DS2-VASc评分为4.3分。12个月时，依度沙班单药治疗组有34名患者（Kaplan-Meier估计，6.8%）和双联抗血栓治疗组有79名患者（16.2%）发生了主要结局事件（风险比，0.44；95% CI，0.30 ~ 0.65；P<0.001）。12个月时两组的主要缺血事件的累积发生率似乎相似。依度沙班单药治疗组有23例患者（Kaplan-Meier估计值，4.7%）和双联抗血栓治疗组有70例患者（14.2%）发生了大出血或有临床意义的非大出血（风险比，0.34；95% CI，0.22 ~ 0.53）。
结论
对于心房颤动合并稳定型冠状动脉疾病的患者，与双联抗血栓治疗相比，依度沙班单药治疗可降低12个月时全因死亡、心肌梗死、卒中、全身性栓塞、计划外紧急血运重建、大出血或临床相关的非大出血构成的复合结局的风险。
12.Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women
AFFILIATIONS
From the Divisions of Preventive Medicine (P.M.R., M.V.M., N.R.C., I.-M.L., J.E.B.) and Cardiovascular Diseases (P.M.R.), Brigham and Women’s Hospital, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (P.M.R., N.R.C., I.-M.L., J.E.B.), and the Department of Laboratory Medicine, Boston Children’s Hospital (N.R.) — all in Boston; and the Faculty of Medicine, University of Porto, Porto, Portugal (N.R.).
Abstract
Background
High-sensitivity C-reactive protein (CRP), low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) levels contribute to 5-year and 10-year predictions of cardiovascular risk and represent distinct pathways for pharmacologic intervention. More information about the usefulness of these biomarkers for predicting cardiovascular risk over longer periods of time in women is needed because early-life intervention represents an important risk-reduction method.
Methods
We measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks.
Results
The mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.
Conclusions
A single combined measure of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels among initially healthy U.S. women was predictive of incident cardiovascular events during a 30-year period. These data support efforts to extend strategies for the primary prevention of atherosclerotic events beyond traditional 10-year estimates of risk.
12.女性的炎症、胆固醇、脂蛋白(a)和30年心血管结局
背景
高敏C反应蛋白(CRP)、低密度脂蛋白(LDL)胆固醇和脂蛋白(a)水平有助于预测5年和10年的心血管风险，并代表了不同的药物干预途径。由于早期干预是降低风险的重要的方法，因此需要更多有关这些生物标记物在预测女性长期心血管风险方面的实用信息。
方法
该研究测量了27,939名最初健康的美国女性的基线高敏CRP、LDL胆固醇和脂蛋白(a)水平，随后对这些女性进行了30年的随访。主要终点是首次发生重大不良心血管事件，包括心肌梗死、冠状动脉血运重建、卒中或心血管原因死亡。研究计算了每种生物标志物五分位数的校正风险比和95%置信区间，以及根据年龄和竞争风险进行校正的30年累积发病率曲线。
结果
参与者的基线平均年龄为54.7岁。在30年的随访期间，发生了3,662 起首次重大心血管事件。高敏CRP、LDL胆固醇和脂蛋白(a)基线水平增加的五分位数均可预测30年风险。将上五分位数与下五分位数进行了比较，主要终点的协变量校正风险比为：高敏CRP 1.70（95% CI，1.52 ~ 1.90），LDL胆固醇1.36（95% CI，1.23 ~ 1.52），脂蛋白(a)1.33（95% CI，1.21 ~ 1.47）。冠心病和卒中的结果似乎与主要终点的结果一致。每种生物标志物都对总体风险有独立的贡献。在包含所有三种生物标志物的模型中获得了最大的风险分布。
结论
在最初健康的美国女性中，高敏性CRP、LDL胆固醇和脂蛋白(a)水平的单一综合指标可预测30年期间的心血管事件发生率。这些数据支持将动脉粥样硬化事件的一级预防策略扩展到传统的10年风险估计值之外。
13.Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B
AFFILIATIONS
From the Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University (J.H., X.L.), and the State Key Laboratory of Organ Failure Research, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Institute of Hepatology, Nanfang Hospital (J.H.), Guangzhou, the Department of Infectious Diseases and Biosafety Emergency Response, Huashan Hospital, Fudan University (W.Z.), the Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine (Q.X.), Roche Holding (Q.B., E.C.), Roche Research and Development Center (C.C., Y.H.), and Takeda APAC Biopharmaceutical Research and Development (Q.B.), Shanghai, the Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, First Hospital of Jilin University, Changchun (R.H.), the Center of Infectious Diseases, Laboratory of Infectious and Liver Disease, Institute of Infectious Diseases, West China Hospital, Sichuan University, Chengdu (H.T.), and the Department of Medicine and State Key Laboratory of Liver Research, Queen Mary Hospital, University of Hong Kong, Hong Kong (M.-F.Y.) — all in China; the Division of Infectious Diseases, University Hospital Álvaro Cunqueiro, Galicia Sur Health Research Institute, Servizo Galego de Saúde–Universidade de Vigo, Vigo, Spain (L.E.M.A.); the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital (S.-S.Y.), and the Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, China Medical University (C.-Y.P.), Taichung, the Department of Internal Medicine, Changhua Christian Hospital, Changhua (W.-W.S.), Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung (W.-L.C.), and National Taiwan University Hospital, Taipei (J.-H.K.) — all in Taiwan; the Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea (D.J.K.); the HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Center and the Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok (A.A.), and the Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai (A.L.) — both in Thailand; Université de Paris-Cité, Department of Hepatology, Assistance Publique–Hôpitaux de Paris, Hôpital Beaujon, Centre de Recherche sur l’Inflammation, INSERM Unité Mixte de Recherche 1149, Paris (T.A.); F. Hoffmann–La Roche, Basel, Switzerland (F. Canducci, M.T.C., F. Chughlay, K.G., N.G., P.K., R.K., M.T.); Roche Products, Welwyn Garden City (S.D., V.P., B.S., R.U., C.W.), and ID Pharma Consultancy, Yelverton (C.W.) — both in the United Kingdom; Enthera Pharmaceuticals, Milan (F. Canducci); Parexel International, Hyderabad, India (A.P.); and the New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand (E.G.).
Abstract
Background
Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.
Methods
We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level,<0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.
Results
Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.
Conclusions
Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon.
13.沙尼西兰联合或不联合免疫调节剂治疗慢性乙型肝炎
背景
沙尼西兰（Xalnesiran）是一种针对乙型肝炎病毒 (HBV) 基因组的保守区域并使多个HBV转录本沉默的小干扰RNA分子，无论是否联合免疫调节剂，它都可能对慢性HBV感染患者有效。
方法
研究者们开展了一项2期、多中心、随机、对照、自适应、开放标签平台试验，评估了48周的治疗效果，治疗组为100 mg剂量的沙尼西兰（第1组）、200 mg剂量的沙尼西兰（第2组）、200 mg剂量的沙尼西兰联合150 mg芦唑莫德（第 3组）、200 mg剂量的沙尼西兰联合180 μg 聚乙二醇干扰素α-2a（第4组），或单独使用核苷或核苷酸类似物(NA)（第5组），治疗对象为经NA治疗获得病毒学抑制的慢性HBV感染者。主要疗效终点是治疗结束后24周乙肝表面抗原 (HBsAg)消失（HBsAg水平<0.05 IU/mL）。该研究还评估了安全性。
结果
在159名参与者中（第1至第5组分别为30、30、34、30和35名），主要终点事件在第1 组为7%（95% CI，1 至 22），第2组为3%（95% CI，0 至 17），第3组为12%（95% CI，3 至 28），第4组为23%（95% CI，10 至 42），第5组为0名（95% CI，0 至 10）。在第1至第5组中，在治疗结束后24周，分别有3%、0、3%、20%和0名参与者发生HBsAg血清转换。仅筛查HBsAg水平低于每毫升1000 IU的参与者才会出现HBsAg消失（伴有或不伴有血清转换）。在第 1至第5组中，分别有17%、10%、18%、50% 和 6%的参与者发生3级或4级不良事件，最常见的事件是丙氨酸氨基转移酶水平升高。
结论
在接受NA疗法抑制病毒的慢性HBV感染者中，使用沙尼西兰加免疫调节剂的治疗导致相当一部分参与者在治疗结束后24周实现了HBsAg消失。然而3级或4级不良事件并不罕见。
December 12, 2024；Volume 391 (23)：2177-2280
在2024年12月12日，共发表24篇文章，其中包括4篇Perspective，5篇Original articles，1篇Review Article，1篇Videos in Clinical Medicine，3篇Images in Clinical Medicine，1篇Case Records of the Massachusetts General Hospital，4篇Editorials，5篇Correspondence。
14.Bedaquiline Monotherapy for Multibacillary Leprosy
AFFILIATION
From the Research Division, Instituto Lauro de Souza Lima, Bauru (J.B., P.S.R.), and Fundação de Dermatologia Tropical e Venereologia Alfredo da Matta, Manaus (P.F.B.R.) — both in Brazil; the Department of Health and Human Services, Health Resources and Services Administration, Health Systems Bureau, National Hansen’s Disease Program, Laboratory Research Branch, Baton Rouge, LA (L.A., R.T.); Translational Medicine and Early Development Statistics (S.Y.), WAVE Team (Z.A., S.R.C., S.K., D.M., J.A.P., M.W.), Janssen Research and Development, San Diego, CA; Janssen Global Public Health, Janssen Research and Development, Titusville, NJ (N.B., R.D.A.); and Janssen Global Public Health, Janssen Pharmaceutica, Beerse, Belgium (E.E., N.L., B.R.).
Abstract
BACKGROUND
Standard multidrug therapy for leprosy may be associated with severe side effects, which add to the stigma and discrimination that affect persons with the disease. In addition, the threat posed by drug-resistant leprosy shows the need for alternative drug combinations and shorter, safer regimens of multidrug therapy.
METHODS
In this open-label, proof-of-concept study conducted in Brazil, we assigned patients with previously untreated multibacillary leprosy to receive bedaquiline monotherapy for 8 weeks. After completing the 8-week course of bedaquiline, the patients started standard multidrug therapy (as defined by the World Health Organization) for leprosy and were followed for 112 weeks. The primary end point was the change from baseline in the odds of positive growth of Mycobacterium leprae in mouse footpads after 8 weeks of bedaquiline therapy. The secondary end point was safety. Exploratory end points included change in the clinical signs and symptoms of leprosy and in the molecular viability of M. leprae (measured by a quantitative reverse-transcriptase–polymerase-chain-reaction assay).
RESULTS
A total of nine patients were included in the modified intention-to-treat analysis. The odds of positive M. leprae growth had decreased from 100% in all the patients at baseline to no growth after 4 weeks of bedaquiline monotherapy. After 7 weeks of treatment, all the patients showed improvement in the appearance of skin lesions as compared with baseline. Seven patients had at least one adverse event (all grade 1 or 2) during treatment.
CONCLUSIONS
In patients with multibacillary leprosy, bedaquiline monotherapy cleared M. leprae by 4 weeks of treatment and led to improvement in the appearance of skin lesions by 7 weeks.
14.贝达喹啉单一疗法治疗多菌性麻风病
背景
麻风的标准多药联合疗法可能伴有严重的副作用，这会增加麻风病患者的耻辱感和被歧视。此外，耐药性麻风带来的威胁表明，需要替代药物组合和更短、更安全的多药联合疗法。
方法
在这项在巴西开展的开放标签概念验证研究中，研究者们安排了之前未接受过治疗的多菌性麻风患者接受8周的贝达喹啉单药治疗。完成8周贝达喹啉疗程后，患者开始接受标准的麻风多药治疗（世界卫生组织定义），并接受112周的随访。主要终点是接受8周贝达喹啉治疗后小鼠足垫中麻风分枝杆菌阳性生长概率相对于基线的变化。次要终点是安全性。探索性终点包括麻风临床体征和症状的变化以及麻风分枝杆菌分子活力的变化（通过定量逆转录聚合酶链反应测定）。
结果
总共有9名患者被纳入了改良意向治疗分析。在贝达喹啉单药治疗4周后，阳性麻风分枝杆菌生长的几率从基线时所有患者的100%降至零生长。经过7周的治疗后，所有患者的皮肤病变外观与基线相比均有所改善。七名患者在治疗期间至少发生过一次不良事件（均为1级或2级）。
结论
对于多菌性麻风病者，贝达喹啉单药治疗4周后可清除麻风分枝杆菌，7周后可改善皮肤病变外观。
15.CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy
AFFILIATION
From the National Amyloidosis Centre, University College London, Royal Free Hospital (M.F., Y.R., J.D.G.), and Richmond Pharmacology (J.T.) — both in London; Brigham and Women’s Hospital, Boston (S.D.S.), and Intellia Therapeutics, Cambridge (J.K., L.W., R.R., D.L., D.S., J.O., A.H., P.Z., Y.X., A.L., A.S.) — both in Massachusetts; the University of Auckland, Auckland, New Zealand (E.J.G.); Umea University, Umea, Sweden (B.P.); Centre Hospitalo–Universitaire de Bicêtre, Assistance Publique–Hôpitaux de Paris, University Paris–Saclay, Le Kremlin–Bicêtre, France (D.A.); and Regeneron Pharmaceuticals, Tarrytown, NY (D.E.G.).
Abstract
Background
Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR).
Methods
In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.
Results
A total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.
Conclusions
In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels.
15.利用Nexiguran Ziclumeran进行CRISPR-Cas9基因编辑治疗ATTR心肌病
背景
伴有转甲状腺素蛋白淀粉样变性的心肌病(ATTR-CM)是一种渐进性疾病，通常会导致死亡。Nexiguran ziclumeran(nex-z)是一种基于CRISPR-Cas9（成簇的规律间隔的短回文重复序列和相关的Cas9核酸内切酶）的试验性疗法，旨在靶向编码转甲状腺素蛋白(TTR)的基因。
方法
在这项1期开放标签试验中，研究者们为ATTR-CM患者进行了单次静脉输注nex-z。主要目标包括评估nex-z对安全性和药效学的影响，包括血清TTR水平。次要终点包括N末端前B型利钠肽(NT-proBNP)水平、高敏性心肌肌钙蛋白T水平、6分钟步行距离和纽约心脏协会(NYHA)分级的变化。
结果
共有36名患者接受了nex-z治疗并完成了至少12个月的随访。在这些患者中，50%为NYHA III级，31%患有变异型ATTR-CM。血清TTR水平相对于基线的平均百分比变化在28天时为-89%（95% CI，-92 ~ -87），在12个月时为-90%（95% CI，-93 ~ -87）。34名患者报告了不良事件。5名患者出现短暂性输液相关反应，2名患者出现短暂性肝酶升高，经评估为与治疗相关。14名患者报告了严重不良事件，其中大多数与ATTR-CM一致。从基线到第12个月，NT-proBNP 水平的几何平均因子变化为1.02（95% CI，0.88 ~ 1.17），高敏性心肌肌钙蛋白T水平的几何平均因子变化为0.95（95% CI，0.89 ~ 1.01）。从基线到第12 个月，6分钟步行距离的中位变化为5米（四分位距，-33 ~ 49）。共有92%的患者NYHA等级有所改善或没有变化。
结论
在这项涉及ATTR-CM患者的1期研究中，单剂量nex-z治疗与短暂的输液相关反应以及血清TTR水平的持续、快速和持久降低有关。
汇报人：刘敏
导师：郑芸
审核：毛敏姿、任建君
