奧希替尼治療切除術後的EGFR突變型非小細胞肺癌
Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer
背景
奧希替尼是既往未經治療的表皮生長因子受體（EGFR）突變陽性晚期非小細胞肺癌（NSCLC）的標準治療。奧希替尼作為輔助治療的療效和安全性尚未明確。Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation–positive advanced non–small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.方法
在此項雙盲、3期試驗中，我們以1:1的比例將完全切除術後的EGFR突變陽性NSCLC患者隨機分組，兩組分別接受為期3年的奧希替尼（每日80 mg）或安慰劑治療。主要終點是II至IIIA期肺癌（根據研究者的判定結果）患者的無病生存期。次要終點包括整個IB至IIIA期肺癌患者人群的無病生存期，以及總生存期和安全性。In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation–positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety.結果
共計682例患者接受了隨機分組（奧希替尼組339例，安慰劑組343例）。第24個月時，奧希替尼組90%（95%置信區間[CI]，84~93）和安慰劑組44%（95% CI，37~51）的II至IIIA期肺癌患者無病生存（疾病復發或死亡的總風險比，0.17；99.06% CI，0.11~0.26；P<0.001）。在整個人群中，奧希替尼組89%（95% CI，85~92）和安慰劑組52%（95% CI，46~58）的患者在24個月時無病生存（疾病復發或死亡的總風險比，0.20；99.12% CI，0.14~0.30；P<0.001）。第24個月時，奧希替尼組98%（95% CI，95~99）和安慰劑組85%（95% CI，80~89）的患者生存且無中樞神經系統轉移（疾病復發或死亡的總風險比，0.18；95% CI，0.10~0.33）。總生存期數據尚不成熟；29例患者死亡（奧希替尼組9例，安慰劑組20例）。未發現新的安全性問題。
Result
A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted.
結論
在IB至IIIA期EGFR突變陽性NSCLC患者中，奧希替尼組患者的無病生存期顯著超過安慰劑組患者。（由阿斯利康資助；ADAURA在ClinicalTrials.gov註冊號為NCT02511106。）
Conclusions
In patients with stage IB to IIIA EGFR mutation–positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)
Yi-Long Wu, Masahiro Tsuboi, Jie He, et al. Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer. DOI:10.1056/NEJMoa2027071本周五 中午十二點 app和官網發布全文中譯
冰島人群對SARS-CoV-2的體液免疫應答
Humoral Immune Response to SARS-CoV-2 in Iceland
背景
關於人體感染SARS-CoV-2後體液免疫應答的特點和持久性，目前仍知之甚少。
Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).方法
我們應用六種檢測法（包括兩種全類別免疫球蛋白[pan-Ig]檢測法）測定了冰島30,576人血清樣本內的抗體；血清反應陽性的判定指標是兩種pan-Ig檢測法的結果均呈陽性。我們檢測了在定量聚合酶鏈反應（qPCR）確診感染後4個月內採集的1237人的2102份樣本，以及曾暴露於SARS-CoV-2的4222名被隔離人員和23,452名未發生已知暴露人員的抗體。
We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin [pan-Ig] assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay. We measured antibodies in 4222 quarantined persons who had been exposed to SARS-CoV-2 and in 23,452 persons not known to have been exposed.
結果
在SARS-CoV-2感染後已康復的1797人中，1215名被檢測者中有1107名（91.1%）呈血清反應陽性；兩種pan-Ig檢測法測出的抗病毒抗體滴度在qPCR確診感染後的2個月期間升高，並在之後的研究期間維持穩定。在被隔離人員中，2.3%呈血清反應陽性；在未發生已知暴露的人員中，0.3%呈陽性。我們估計有0.9%的冰島人曾感染SARS-CoV-2，其中0.3%導致了死亡。我們還估計在冰島的所有SARS-CoV-2感染者中，有56%曾通過qPCR確診，有14%發生於未接受qPCR檢測的被隔離人員（或者qPCR檢測後結果並非陽性者），30%發生於未被隔離且未接受qPCR檢測的人員。
Result
Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR.結論
我們的研究結果表明，針對SARS-CoV-2的抗病毒抗體在確診感染後4個月內並未下降。我們估計因感染SARS-CoV-2而死亡的風險為0.3%，冰島感染者中有44%未經過qPCR確診。
Conclusions
Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR.Daniel F. Gudbjartsson, Gudmundur L. Norddahl, Pall Melsted, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. DOI: 10.1056/NEJMoa2026116
本周五 中午十二點 app和官網發布全文中譯
小劑量艾多沙班治療高齡患者心房顫動
Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation
背景
通過適當口服抗凝來預防高齡心房顫動患者的卒中有難度，原因是擔心患者發生出血。
Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.方法
我們開展了一項3期、多中心、隨機、雙盲、安慰劑對照的事件驅動試驗，試驗納入了不適合採用已批准的卒中預防劑量進行口服抗凝治療的日本高齡（年齡≥80歲）非瓣膜性心房顫動患者，目的是比較每日一次15 mg艾多沙班與安慰劑的效果。主要療效終點是由卒中或體循環栓塞構成的複合終點，主要安全性終點是國際血栓與止血學會（International Society on Thrombosis and Haemostasis）定義的大出血。
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.結果
共計984例患者被隨機分配（1:1比例）接受15 mg日劑量的艾多沙班（492例患者）或安慰劑（492例患者）。681例患者完成試驗，303例患者停止試驗（158例退出，135例死亡，10例其他原因）；兩組中停止試驗的患者數量相似。艾多沙班組和安慰劑組患者卒中或體循環栓塞的年發生率分別為2.3%和6.7%（風險比，0.34；95%置信區間[CI]，0.19~0.61；P<0.001），艾多沙班組和安慰劑組患者大出血的年發生率分別為3.3%和1.8%（風險比，1.87；95% CI，0.90~3.89；P=0.09）。艾多沙班組的消化道出血事件發生率明顯高於安慰劑組。兩組的全因死亡率無明顯差異（艾多沙班組9.9%，安慰劑組10.2%；風險比，0.97；95% CI，0.69~1.36）。
Result
A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P=0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).
結論
在不適合接受常規劑量口服抗凝劑的日本高齡非瓣膜性心房顫動患者中，在預防卒中或體循環栓塞方面，每日一次15 mg的艾多沙班優於安慰劑，且艾多沙班組的大出血發生率並未顯著高於安慰劑組。（由第一三共株式會社資助；在ClinicalTrials.gov註冊號為NCT02801669。）
Conclusions
In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.)Ken Okumura, Masaharu Akao, Tetsuro Yoshida, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. DOI:10.1056/NEJMoa2012883外顯子組測序在非免疫性胎兒水腫產前診斷中的應用
Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis
背景
胎兒畸形的原因大多無法在產前確定。外顯子組測序已改變了嬰兒出生後的遺傳學診斷，但其在產前診斷中的作用才逐漸顯現。非免疫性胎兒水腫（NIHF）是一種通常致命的胎兒異常，有許多遺傳原因；外顯子組測序對其診斷有多大幫助尚不明確。
The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.方法
我們評估了連續127例不明原因的NIHF病例，NIHF的定義為有胎兒腹水、胸腔或心包積液、皮膚水腫、囊狀水瘤、胎兒頸後透明層厚度增加或上述多種情況。主要結局是外顯子組測序對遺傳變異的診斷率，遺傳變異根據美國醫學遺傳學和基因組學會（American College of Medical Genetics and Genomics）標準分成致病性和可能致病性兩類。次要結局是特定遺傳病相關病例的百分比和遺傳的變異的比例。
We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.結果
在127個病例中，我們識別出37例（29%）存在具有診斷意義的遺傳變異，包括影響RAS-MAPK細胞信號通路的疾病（稱作RAS病）（佔遺傳診斷的30%），先天性代謝病和肌肉骨骼疾病（各佔11%）的遺傳變異，以及淋巴、神經發育、心血管和血液疾病（各佔8%）等。其預後從相對較輕的結局至圍產期死亡不等。在存在具有診斷意義的遺傳變異的病例中，68%（25/37）為常染色體顯性（其中12%來自遺傳，88%為新發），27%（10/37）為常染色體隱性（其中95%來自遺傳，5%為新發），1例為遺傳的X染色體連鎖隱性，1例的遺傳情況不確定。我們識別出另外12例存在可能具有診斷意義的變異。
Result
In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS–MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.
結論
在這項包含127名不明原因NIHF胎兒的病例系列研究中，我們在約三分之一病例識別出具有診斷意義的遺傳變異。（由UCSF母胎精準醫學中心[UCSF Center for Maternal-Fetal Precision Medicine]等資助；在ClinicalTrials.gov註冊號為NCT03412760。）
Conclusions
In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal–Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.)關注《NEJM醫學前沿》
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