2024年9月26日 |《新英格兰医学杂志》英文音频和中英文摘要

应用PSA和MRI进行四年前列腺癌筛查的结果

Results after Four Years of Screening for Prostate Cancer with PSA and MRI

背景

关于应用磁共振成像（MRI）进行前列腺癌筛查的有效性和安全性，目前仍需后续筛查研究提供数据。

Data on the efficacy and safety of screening for prostate cancer with magnetic resonance imaging (MRI) are needed from studies of follow-up screening.

方法

在2015年启动的一项基于人群的试验中，我们邀请50~60岁男性接受前列腺特异性抗原（PSA）筛查。PSA水平达到或超过3 ng/mL的男性接受前列腺MRI检查。男性被随机分配到系统性活检组（接受系统性活检，如果MRI发现可疑病变，则接受靶向活检）或MRI靶向活检组（只接受MRI靶向活检）。根据PSA水平的不同，每次访视时邀请男性在2、4或8年后接受再次筛查。主要结局是检测出无临床意义（国际泌尿病理学会[ISUP，International Society of Urological Pathology]分级为1级）的前列腺癌；检测出有临床意义（ISUP分级≥2级）的前列腺癌是次要结局，同时还评估了检测出临床晚期或高危（转移性或ISUP分级4级或5级）前列腺癌。

In a population-based trial that started in 2015, we invited men who were 50 to 60 years of age to undergo prostate-specific antigen (PSA) screening. Men with a PSA level of 3 ng per milliliter or higher underwent MRI of the prostate. Men were randomly assigned to the systematic biopsy group, in which they underwent systematic biopsy and, if suspicious lesions were found on MRI, targeted biopsy, or the MRI-targeted biopsy group, in which they underwent MRI-targeted biopsy only. At each visit, men were invited for repeat screening 2, 4, or 8 years later, depending on the PSA level. The primary outcome was detection of clinically insignificant (International Society of Urological Pathology [ISUP] grade 1) prostate cancer; detection of clinically significant (ISUP grade ≥2) cancer was a secondary outcome, and detection of clinically advanced or high-risk (metastatic or ISUP grade 4 or 5) cancer was also assessed.

结果

经过中位3.9年（每组约26,000人-年）随访，MRI靶向活检组6575名男性中的185人（2.8%）和系统性活检组6578名男性中的298人（4.5%）被检测出前列腺癌。与系统性活检组相比，MRI靶向活检组检测出无临床意义前列腺癌的相对危险度为0.43（95%置信区间[CI]，0.32~0.57；P<0.001），再次筛查时的相对危险度低于第一轮筛查时（相对危险度，0.25  vs.  0.49），诊断出有临床意义前列腺癌的相对危险度为0.84（95% CI，0.66~1.07）。MRI靶向活检组检测出晚期或高危前列腺癌（通过筛查检测出或发生间期癌）15例，系统性活检组为23例（相对危险度，0.65；95% CI，0.34~1.24）。该试验发生5起重度不良事件（系统性活检组3起，MRI靶向活检组2例）。

Result

After a median follow-up of 3.9 years (approximately 26,000 person-years in each group), prostate cancer had been detected in 185 of the 6575 men (2.8%) in the MRI-targeted biopsy group and 298 of the 6578 men (4.5%) in the systematic biopsy group. The relative risk of detecting clinically insignificant cancer in the MRI-targeted biopsy group as compared with the systematic biopsy group was 0.43 (95% confidence interval [CI], 0.32 to 0.57; P<0.001) and was lower at repeat rounds of screening than in the first round (relative risk, 0.25 vs. 0.49); the relative risk of a diagnosis of clinically significant prostate cancer was 0.84 (95% CI, 0.66 to 1.07). The number of advanced or high-risk cancers detected (by screening or as interval cancer) was 15 in the MRI-targeted biopsy group and 23 in the systematic biopsy group (relative risk, 0.65; 95% CI, 0.34 to 1.24). Five severe adverse events occurred (three in the systematic biopsy group and two in the MRI-targeted biopsy group).

结论

在此项试验中，将MRI阴性患者豁免活检，可以将诊断出的无临床意义前列腺癌减少一半以上，并且筛查时诊断出不可治愈前列腺癌或发生间期癌的风险非常低。（由Karin and Christer Johansson基金会等资助；GÖTEBORG-2在ISRCTN注册号为ISRCTN94604465）。

Conclusions

In this trial, omitting biopsy in patients with negative MRI results eliminated more than half of diagnoses of clinically insignificant prostate cancer, and the associated risk of having incurable cancer diagnosed at screening or as interval cancer was very low. (Funded by Karin and Christer Johansson’s Foundation and others; GÖTEBORG-2 ISRCTN registry number, ISRCTN94604465.)

齐瑞索韦治疗感染呼吸道合胞病毒住院婴儿试验

Ziresovir in Hospitalized Infants with Respiratory Syncytial Virus Infection

背景

呼吸道合胞病毒（RSV）是导致婴儿重病的主要原因，目前尚无有效治疗方法。一项2期试验提示，齐瑞索韦对因感染RSV而住院的婴儿可能有效。

在中国进行的一项多中心、双盲、随机、安慰剂对照3期试验中，我们纳入了因感染RSV而住院的1~24月龄参与者。以2:1比例随机分配参与者服用齐瑞索韦（根据体重，剂量为10~40 mg）或安慰剂，每日两次，用药5天。主要终点是Wang细支气管炎临床评分（总分范围为0~12分，评分较高表示症状和体征较严重）从基线到第3天（定义为首剂给药后48小时）的变化。意向性治疗人群包括确诊感染RSV并接受至少一剂齐瑞索韦或安慰剂治疗的所有参与者；安全性人群包括接受至少一剂齐瑞索韦或安慰剂治疗的所有参与者。

Methods

In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted in China, we enrolled participants 1 to 24 months of age who were hospitalized with RSV infection. Participants were randomly assigned, in a 2:1 ratio, to receive ziresovir (at a dose of 10 to 40 mg, according to body weight) or placebo, administered twice daily, for 5 days. The primary end point was the change from baseline to day 3 (defined as 48 hours after the first administration) in the Wang bronchiolitis clinical score (total scores range from 0 to 12, with higher scores indicating greater severity of signs and symptoms). The intention-to-treat population included all the participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo; the safety population included all the participants who received at least one dose of ziresovir or placebo.

意向性治疗人群包括244名参与者，安全性人群包括302名参与者。齐瑞索韦组第3天Wang细支气管炎临床评分相对于基线的降幅显著大于安慰剂组（－3.4分[95%置信区间{CI}，－3.7~－3.1] vs. －2.7分[95% CI，－3.1~－2.2]；差异，－0.8分[95% CI，－1.3~－0.3]；P=0.002）。齐瑞索韦组第5天RSV病毒载量的降幅大于安慰剂组（－2.5 vs. －1.9 log10 copies/mL；差异，－0.6 log10 copies/mL [95% CI，－1.1~－0.2]）。本试验在预设亚组中观察到改善效果，其中包括基线细支气管炎评分至少为8分的参与者以及6月龄或更小的参与者。与药物或安慰剂相关的不良事件发生率为齐瑞索韦组16%，安慰剂组13%。研究者判定与药物或安慰剂相关的最常见不良事件包括腹泻（两组发生率分别为4%和2%）、肝酶水平升高（3%和3%）和皮疹（2%和1%）。齐瑞索韦组有15名参与者（9%）检测出耐药相关突变。

Result

The intention-to-treat population included 244 participants, and the safety population included 302. The reduction from baseline in the Wang bronchiolitis clinical score at day 3 was significantly greater with ziresovir than with placebo (−3.4 points [95% confidence interval {CI}, −3.7 to −3.1] vs. −2.7 points [95% CI, −3.1 to −2.2]; difference, −0.8 points [95% CI, −1.3 to −0.3]; P=0.002). The reduction in the RSV viral load at day 5 was greater in the ziresovir group than in the placebo group (−2.5 vs. −1.9 log10 copies per milliliter; difference, −0.6 log10 copies per milliliter [95% CI, −1.1 to −0.2]). Improvements were observed in prespecified subgroups, including in participants with a baseline bronchiolitis score of at least 8 and in those 6 months of age or younger. The incidence of adverse events related to the drug or placebo was 16% with ziresovir and 13% with placebo. The most common adverse events that were assessed by the investigator as being related to the drug or placebo were diarrhea (in 4% and 2% of the participants, respectively), an elevated liver-enzyme level (in 3% and 3%, respectively), and rash (in 2% and 1%). Resistance-associated mutations were identified in 15 participants (9%) in the ziresovir group.

结论

齐瑞索韦可减轻因感染RSV而住院的婴幼儿的细支气管炎症状和体征。未发现任何安全问题。（由上海爱科百发生物医药技术股份有限公司资助；AIRFLO在ClinicalTrials.gov注册号为NCT04231968）

成人血友病B患者的fidanacogene elaparvovec基因疗法

Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B

背景

fidanacogene elaparvovec是治疗血友病B的腺相关病毒（AAV）基因疗法载体，含有高活性人类因子Ⅸ变异体（FIX-R338L/FIX-Padua），在1~2a期研究中表现出持续因子Ⅸ活性。

我们对fidanacogene elaparvovec开展了3期开放标签研究，起剂量为5×10¹¹载体基因组拷贝/kg体重。以下患者可接受筛选：年龄18~65岁男性，患血友病B，接受过至少6月龄的因子Ⅸ浓缩物预防性用药，且因子Ⅸ水平≤2%。进行非劣效性检验的主要终点是与预防性用药的导入期相比，患者接受fidanacogene elaparvovec治疗后第12周至第15个月的年出血率（接受治疗和未接受治疗的出血次数）。本试验还评估了优效性、其他疗效终点和安全性。

Methods

We conducted a phase 3 open-label study of fidanacogene elaparvovec at a dose of 5×10¹¹ vector genome copies per kilogram of body weight. Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were eligible for screening if they had received at least 6 months of therapy with prophylactic factor IX concentrate. The primary end point, tested for noninferiority, was the annualized bleeding rate (treated and untreated bleeding episodes) from week 12 to month 15 after treatment with fidanacogene elaparvovec as compared with the prophylaxis lead-in period. Superiority, additional efficacy end points, and safety were also assessed.

在导入研究期间接受筛选的316名男性中，204人（64.6%）不符合纳入标准；其中188人（59.5%）是因为存在抗AAV中和抗体而不符合纳入标准。在45名接受fidanacogene elaparvovec治疗的参与者中，44人完成了至少15个月随访。所有出血的年出血率降低了71%，从基线时的4.42次（95%置信区间[CI]，1.80~7.05）降至接受基因疗法后的1.28次（95% CI，0.57~1.98），两组差异为－3.15次（95% CI，－5.46~－0.83；P=0.008）。这一结果表明，fidanacogene elaparvovec不劣于预防性用药，并且优于预防性用药。15个月时，根据一期SynthASil检测结果，因子Ⅸ平均活性为26.9%（中位数，22.9%；范围，1.9~119.0）。共计28名参与者（62%）因氨基转移酶水平升高或因子Ⅸ水平降低（或两者皆有），在11天~123天之间开始接受糖皮质激素治疗。本试验未观察到与输液相关的严重不良事件、血栓事件、因子Ⅸ抑制物生成或恶性疾病。

Result

Of 316 men who underwent screening for the lead-in study, 204 (64.6%) were not eligible; 188 (59.5%) of those were ineligible owing to the presence of anti-AAV neutralizing antibodies. Of the 45 participants who received fidanacogene elaparvovec, 44 completed at least 15 months of follow-up. The annualized rate of bleeding for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of −3.15 episodes (95% CI, −5.46 to −0.83; P=0.008). This result shows the noninferiority and superiority of fidanacogene elaparvovec to prophylaxis. At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay. A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days. No infusion-related serious adverse events, thrombotic events, development of factor IX inhibitors, or malignant conditions were observed.

结论

在治疗血友病B参与者方面，fidanacogene elaparvovec优于预防性用药，可减少出血并稳定因子Ⅸ表达。（由辉瑞公司资助；BENEGENE-2在ClinicalTrials.gov注册号为NCT03861273）。

抗TL1A单克隆抗体tulisokibart治疗溃疡性结肠炎的2期试验

Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis

背景

tulisokibart是一种在研的肿瘤坏死因子样细胞因子1A（TL1A）单克隆抗体，目前正开发其用于治疗中度至重度活动性溃疡性结肠炎。现已设计出基于基因的诊断检测法，用于识别应答概率较高的患者。

我们将糖皮质激素依赖或者常规或先进疗法失败的溃疡性结肠炎患者随机分组，分别静脉注射tulisokibart（第1天1000 mg，第2、6和10周500 mg）或安慰剂。队列1包括所有患者，无论其应答概率检测结果如何。队列2只包括应答概率检测呈阳性的患者。主要分析在队列1中进行；主要终点是第12周时的临床缓解。在预设分析中，将队列1和队列2应答概率检测呈阳性的患者合并。

Methods

We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses.

在队列1中，共计135例患者接受了随机分组。接受tulisokibart治疗的患者达到临床缓解的比例显著高于接受安慰剂治疗的患者（26% vs. 1%；差异，25个百分点；95%置信区间[CI]，14~37；P<0.001）。在队列2中，共计43例患者接受了随机分组。在两个队列中，共计75例应答概率检测呈阳性的患者接受了随机分组。在应答概率检测呈阳性的患者中（队列1和队列2合并），接受tulisokibart治疗的患者达到临床缓解的比例高于接受安慰剂治疗的患者（32% vs. 11%；差异，21个百分点；95% CI，2~38；P=0.02）。在本试验纳入的所有患者中，tulisokibart组和安慰剂组的不良事件发生率相似；大多数不良事件的严重程度为轻度至中度。

Result

In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI], 14 to 37; P<0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI, 2 to 38; P=0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity.

结论

在此项短期试验中，tulisokibart在诱导中度至重度活动性溃疡性结肠炎患者达到临床缓解方面比安慰剂更有效。（由默克公司子公司Prometheus Biosciences资助；ARTEMIS-UC在ClinicalTrials.gov注册号为NCT04996797）。