聚焦超聲丘腦底部切開術治療帕金森病的隨機試驗
Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson’s Disease
背景
底丘腦核是深部腦刺激治療帕金森病主要運動表現的首選神經外科靶區。聚焦超聲是一種影像學引導的方法，用於在深部腦結構（包括丘腦底核）產生治療性毀損。The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson’s disease. Focused ultrasound is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus.方法
本試驗納入有藥物未能完全控制的運動體徵或不適合深部腦刺激手術的顯著不對稱性帕金森病患者。我們以2:1的比例將其隨機分配接受主要運動體徵對側的聚焦超聲丘腦底部切開術或假手術。主要療效結局是停藥狀態下，較嚴重一側的運動障礙學會-聯合帕金森病評價量表（Movement Disorder Society-Unified Parkinson’s Disease Rating Scale，MDS-UPDRS）運動評分（即第III部分）從基線至4個月所發生變化的組間差異。主要安全性結局（手術相關併發症）在4個月時評估。We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months.結果
在本試驗納入的40例患者中，27例被分配接受聚焦超聲丘腦底部切開術（活性治療），13例被分配接受假手術（對照）。在活性治療組中，較嚴重一側的平均MDS-UPDRS III評分從基線時的19.9分降低至4個月時的9.9分（最小二乘均值差異，9.8分；95%置信區間[CI]，8.6~11.1），而對照組從18.7分降低至17.1分（最小二乘均值差異，1.7分；95% CI，0.0~3.5）；組間差異為8.1分（95% CI，6.0~10.3；P<0.001）。活性治療組的不良事件包括6例患者在停藥狀態下，6例患者在用藥狀態下發生運動障礙，並且4個月時分別有3例患者和1例患者的運動障礙仍持續；5例患者出現治療側無力，並且4個月時有2例患者的無力仍持續；15例患者出現語言障礙，並且4個月時3例患者的語言障礙仍持續；3例患者出現面部無力，並且4個月時1例患者的面部無力仍持續；13例患者出現步態障礙，並且4個月時2例患者的步態障礙仍持續。在活性治療組的6例患者中，一些障礙在12個月時仍存在。
Result
Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval [CI], 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months.
結論
在經過選擇，有不對稱體徵的患者中，一側半球的聚焦超聲丘腦底部切開術改善了帕金森病的運動表現。不良事件包括語言和步態障礙、治療側無力和運動障礙。（由Insightec等資助；在ClinicalTrials.gov註冊號為NCT03454425。）
Conclusions
Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson’s disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.)
資源匱乏國家通過地塞米松產前用藥預防早期早產
Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries
背景
對於有早產風險的資源匱乏國家女性，糖皮質激素產前用藥的安全性和有效性尚不明確。
The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain.方法
我們在妊娠26周0日至33周6日，並且有早產風險的孕婦中開展了一項多國、隨機試驗。參與者被分配接受地塞米松或安慰劑肌內注射。主要結局包括單獨新生兒死亡、死產或新生兒死亡和可能的孕產婦細菌性感染；我們通過優效性分析方法評估了單獨新生兒死亡以及死產或新生兒死亡，並通過非劣效性分析方法評估了可能的孕產婦細菌性感染（利用相對尺度上1.25的預設界值）。
We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale.
結果
來自孟加拉國、印度、肯亞、奈及利亞和巴基斯坦29家二級和三級醫院的共計2852名女性（及其3070名胎兒）接受了隨機分組。在第二次期中分析時，本試驗因藥物有益而提前終止。地塞米松組1417名嬰兒中的278名（19.6%）和安慰劑組1406名嬰兒中的331名（23.5%）發生了新生兒死亡（相對危險度，0.84；95%置信區間[CI]，0.72~0.97；P=0.03）。兩組分別有1532名胎兒和嬰兒中的393名（25.7%）以及1519名胎兒和嬰兒中的444名（29.2%）發生了死產或新生兒死亡（相對危險度，0.88；95% CI，0.78~0.99；P=0.04）；可能的孕產婦細菌性感染的發生率分別為4.8%和6.3%（相對危險度，0.76；95% CI，0.56~1.03）。不良事件發生率無顯著組間差異。
Result
A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P=0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events.結論
在有早產風險的資源匱乏國家女性中，與使用安慰劑相比，使用地塞米松顯著降低了單獨新生兒死亡以及死產或新生兒死亡的風險，與此同時可能的孕產婦細菌性感染的發生率未增加。（由比爾及梅林達·蓋茨基金會[Bill and Melinda Gates Foundation]和世界衛生組織資助；在澳大利亞和紐西蘭臨床試驗註冊系統註冊號為ACTRN12617000476336；在印度臨床試驗註冊系統註冊號為CTRI/2017/04/008326。）
Conclusions
Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry–India number, CTRI/2017/04/008326.)The WHO ACTION Trials Collaborators. Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries. DOI: 10.1056/NEJMoa2022398
首次緩解期急性髓系白血病應用口服阿扎胞苷維持治療
Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission
背景
雖然誘導化療可使許多老年急性髓系白血病（AML）患者達到緩解，但復發的情況常見，且總生存期較短。
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.方法
我們開展了一項3期、隨機、雙盲、安慰劑對照試驗，本試驗將阿扎胞苷口服製劑（CC-486，一種與阿扎胞苷注射劑不具有生物等效性的低甲基化藥物）作為強化化療後首次緩解期的AML患者的維持治療。我們將年齡≥55歲、處於完全緩解期（全血細胞計數恢復或未恢復）且不適合接受造血幹細胞移植的患者隨機分組，兩組分別接受每日1次CC-486（300 mg）或安慰劑治療，每28天一個周期，每個周期用藥14天。主要終點是總生存期。次要終點包括無復發生存期和健康相關生活質量。
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.結果
共計472例患者被隨機分組；238例被分配至CC-486組，234例被分配至安慰劑組。中位年齡為68歲（範圍，55~86）。在CC-486組中，從隨機分組開始計算的中位總生存期顯著超過安慰劑組（分別為24.7個月和14.8個月；P<0.001）。CC-486組的中位無復發生存期也顯著超過安慰劑組（分別為10.2個月和4.8個月；P<0.001）。CC-486在總生存期和無復發生存期方面有益處見於根據基線特徵定義的大多數亞組。兩組最常見的不良事件均為1級或2級胃腸道事件。常見的3級或4級不良事件包括中性粒細胞減少（CC-486組41%的患者和安慰劑組24%的患者）和血小板減少（分別為22%和21%）。患者在CC-486治療期間可保持總體健康相關生活質量。
Result
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
結論
在化療後緩解期的老年AML患者中，與安慰劑相比，CC-486維持治療與顯著較長的總生存期和無復發生存期相關。副作用主要包括胃腸道症狀和中性粒細胞減少。患者在整個治療期間可維持生活質量指標。（由賽爾基因[Celgene]資助；QUAZAR AML-001在ClinicalTrials.gov註冊號為NCT01757535。）
Conclusions
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.)本周五 中午十二點 app和官網發布全文中譯
紫杉醇塗層裝置用於外周動脈疾病患者後的死亡率
Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease
背景
最近一項薈萃分析的結果引起了人們的關注，即使用紫杉醇塗層血管成形術球囊和支架對有症狀的外周動脈疾病實施下肢血管內介入治療與死亡風險增加相關。
The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.
方法
我們對一項基於登記系統的多中心、隨機、開放標籤臨床試驗進行了計劃外的期中分析。分析時，2289例患者已被隨機分配接受藥物塗層裝置（藥物塗層裝置組，1149例患者）或無塗層裝置治療（無塗層裝置組，1140例患者）。隨機分組根據疾病嚴重程度（依據患者有慢性肢體重度缺血[1480例患者]還是間歇性跛行[809例患者]）進行分層。此項期中分析的單一終點為全因死亡。We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated–device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.結果
無患者失訪。紫杉醇被用作所有藥物塗層裝置的塗層藥物。在平均2.49年隨訪期間，574例患者死亡，包括藥物塗層裝置組293例患者（25.5%）和無塗層裝置組281例患者（24.6%）（風險比，1.06；95%置信區間，0.92~1.22）。1年時，藥物塗層裝置組和無塗層裝置組的全因死亡率分別為10.2%（117例患者）和9.9%（113例患者）。在整個隨訪期間，在慢性肢體重度缺血患者中（藥物塗層裝置組33.4%[249例患者]和無塗層裝置組33.1%[243例患者]）和在間歇性跛行患者中（分別為10.9%[44例患者]和9.4%[38例患者]），兩個治療組的死亡率均無顯著差異。
Result
No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated–device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated–device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated–device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).
結論
在這項隨機試驗中，外周動脈疾病患者接受了紫杉醇塗層或無塗層血管內裝置治療。全因死亡率的計劃外期中分析結果表明，1~4年隨訪期間的死亡率無組間差異。（由瑞典研究理事會[Swedish Research Council]等資助；在ClinicalTrials.gov註冊號為NCT02051088。）
Conclusions
In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.)妊娠期癲癇發作頻率和抗癲癇治療的變化
Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy
背景
女性癲癇患者的妊娠期癲癇發作頻率變化情況研究受到限制，原因是缺乏適當的非妊娠對照組來提供兩組中癲癇發作頻率的自然過程數據。
Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups.
方法
在這項前瞻性、觀察性、多中心隊列研究中，我們比較了妊娠期（截至圍產期，即產後6周）（時期1）的癲癇發作頻率和產後期（之後7.5個月）（時期2）的癲癇發作頻率。本試驗納入了非妊娠的女性癲癇患者作為對照，她們在18個月期間接受了類似隨訪。主要結局是在時期1，意識受損性癲癇發作頻率高於時期2的女性百分比。我們還比較了時期1前9個月期間，兩組中抗癲癇藥劑量的變化情況。In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy) (epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the two groups during the first 9 months of epoch 1.結果
本試驗納入了患癲癇的351名孕婦和109名對照女性。在發生意識受損性癲癇發作，並且兩個時期均獲得數據的299名孕婦和93名對照女性中，70名孕婦（23%）和23名對照女性（25%）在時期1的癲癇發作頻率高於時期2（比值比，0.93；95%置信區間[CI]，0.54~1.60）。在時期1（即孕婦妊娠期間），74%孕婦和31%對照女性的抗癲癇藥劑量至少變化了1次（比值比，6.36；95% CI，3.82~10.59）。
Result
We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the two epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 pregnant women (23%) and in 23 controls (25%) (odds ratio, 0.93; 95% confidence interval [CI], 0.54 to 1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82 to 10.59).
結論
在女性癲癇患者中，妊娠期癲癇發作頻率高於產後期的百分比與時期1癲癇發作頻率高於時期2的非妊娠女性百分比相似。在相似時間段內，孕婦的抗癲癇藥劑量變化頻率高於非妊娠女性。（由美國國立衛生研究院資助；MONEAD在ClinicalTrials.gov註冊號為NCT01730170。）
Conclusions
Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.)Page B. Pennell, Jacqueline A. French, Ryan C. May, et al. Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy. DOI: 10.1056/NEJMoa2008663本周五 中午十二點 app和官網發布全文中譯
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