Preserved ratio impaired spirometry (PRISm) is a prevalent yet under-researched state of diminished lung function, which has been proposed as a pre-clinical abnormal spirometry associated with chronic obstructive pulmonary disease (COPD) or early-stage COPD. PRISm is closely associated with cardiovascular disease. Preventing and improving quality of life in PRISm subjects is important. We aimed to examined the relationship between American Heart Association’s Life’s Essential 8 (LE8) and PRISm. This cross-sectional study utilized data of 2,869 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) in 2007–2012. Multivariable logistic regression models were employed to examine the association between LE8 score, health behavior score, health factor score, each component of LE8 score, and PRISm. Moreover, the study explored this correlation in greater depth using restricted cubic spline curves and subgroup analyses. Of the 2,869 participants, the mean age was 44.09 ± 0.44 years, and 316 (11.01%) were defined as having PRISm. In fully adjusted models, higher LE8 scores were associated with a reduced odds ratio for PRISm (OR = 0.97; 95% CI, 0.96–0.98). A linear relationship between the LE8 score and PRISm was observed. Similar patterns emerged for health behavior and health factor subscores, with a particularly stronger correlation between health factors and PRISm. In the subgroup analysis, the inverse association between LE8 and PRISm was significantly more pronounced among those with high income. A higher LE8 score was associated with a lower likelihood of developing PRISm. Promoting optimal adherence to the LE8 metrics may improve PRISm and offers a meaningful approach for its prevention and management.

MethodsCNKI, Wanfang, VIP, Sinomed, Pubmed, Web of Science, Embase, and other databases were searched. The retrieval time was from the establishment of the database to January 31, 2024. We included all predictive models for the invasion of ground-glass pulmonary nodules established. The modeling group was patients with a pathological diagnosis of ground-glass pulmonary nodules. Two researchers screened the literature, established an Excel table for information extraction, used SPSS 25.0 to perform frequency statistics of each independent risk factor, and used Revman 5.4 software for meta-analysis.ResultsA total of 29 articles were included, involving 30 independent risk factors, with a cumulative frequency of 99 times. There were 16 risk factors with a frequency of ≥2 times, a total of 85 times, accounting for 85.86%. The meta-analysis showed the following: average CT value (MD = 75.57 HU, 95%CI: 44.40–106.75), maximum diameter (MD = 4.99 mm, 95%CI: 4.22–5.77), vascular convergence sign (OR = 11.16, 95%CI: 6.71–18.56), lobulation sign (OR = 3.80, 95%CI: 1.59–9.09), average diameter (MD = 4.46 mm, 95%CI: 3.44–5.48), maximum CT value (MD = 112.52 HU, 95%CI: 8.08–216.96), spiculation sign (OR = 4.46, 95%CI: 2.03–9.81), volume (MD = 1,069.37 mm3, 95%CI: 1,025.75–1,112.99), vacuole sign (OR = 6.15, 95%CI: 2.70–14.01), CTR ≥0.5 (OR = 7.24, 95%CI: 3.35–15.65), vascular type [types III and IV] (OR = 13.62, 95%CI: 8.85–20.94), pleural indentation (OR = 6.92, 95%CI: 2.69–17.82), age (MD = 4.18years, 95%CI: 1.70–6.65), and mGGN (OR = 3.62, 95%CI: 2.36–5.56) were risk factors for infiltration of ground-glass nodules. The overall risk of bias in the methodological quality evaluation of the included studies was small, and the AUC value of the model was 0.736–0.977.ConclusionThe included model has a good predictive performance for the invasion of ground-glass nodules. The independent risk factors included in the model can help medical workers to identify the high-risk groups of invasive lung cancer in ground-glass nodules in time and improve the prognosis.

BackgroundAsthma, depression, and sleep problems are three significant public health issues that are closely interrelated. This study aims to explore the relationship between depression, sleep status and asthma, as well as the potential interaction among these conditions and their effects on asthma.MethodThis cross-sectional study utilized data from the 2005-2008 National Health and Nutritional Examination Survey, including information on asthma, depression, sleep status and confounding factors. Multivariate logistic regression analyses were conducted to investigate the relationship between depression, sleep status, and asthma. Subgroup analyses were conducted to test the p-interaction between depression and each stratified variable. Additionally, both multiplicative and additive approaches were employed to assess the interaction between depression and sleep status on asthma, as well as to quantify their combined effects.ResultsA total of 8,327 participants (mean age 46.53 years) were included in this study. Compared to the individuals without depression, those with depression have an increased risk of asthma [Odds ratio (OR) = 1.57, 95% Confidence interval (CI) = 1.22-2.03], and an increase in the severity of depressive symptoms is associated with a higher risk of developing asthma. Additionally, poor sleep quality, sleep disorders, and insufficient sleep was associated with an increased risk of asthma. Effect modification was observed between depression and PIR status, smoking status, and sleep disorders in relation to asthma (p-interaction <0.05). Moreover, we found a positive interaction between severe depression and excessive sleep (OR = 29.07, 95% CI = 3.24-260.38). Furthermore, we observed the quantitative additive interaction indicators between moderately severe depression and insufficient sleep [Relative excess risk due to interaction (RERI) = 1.63, 95%CI = 0.18-3.83; Attributable proportion (AP) = 0.51, 95%CI = 0.15-0.87; Synergy index (SI) = 3.92, 95%CI = 1.65-23.50] influencing asthma risk.ConclusionOur study revealed distinct associations between depression, the severity of depressive symptoms, poor sleep quality, sleep disorders, and insufficient sleep with asthma. Additionally, there was an interaction between moderately severe depression and insufficient sleep on asthma. Psychological and sleep assessment are essential in asthma management. Clinicians should consider the potential risk of depression and sleep problems in asthma patients and intervene. Further longitudinal research is needed to better understand the pathophysiological mechanisms behind the interactions between asthma, depression, and sleep problems.

Objective We aimed to observe the clinical efficacy of treating medium-risk solid pulmonary nodules based on patient’s pathogenesis state.Methods A prospective randomized controlled study was conducted to select patients with medium-risk solid pulmonary nodules who were admitted to either Dongfang Hospital of Beijing University of Chinese Medicine or Beijing Shijitan Hospital Affiliated to Capital Medical University from September 2020 to July 2022（128 cases in total）. The patients were randomly divided using the random number table method into the experimental group（85 cases） and the blank control group（43 cases） at a 2:1 ratio. We diagnosed patients with（ⅰ） single state: qi deficiency, yin deficiency, yang deficiency, qi stagnation, and dampness-heat state,（ⅱ） combined state, or（ⅲ） a general state: if the patients did not meet any of the diagnosis criteria. Patients in the experimental group were treated with additional Sanjie basic prescription（Processed pinellia, Arisaema with bile, Balloon flower, Tuckahoe, Raw oyster, Radix notoginseng） according to the state at the time of consultation, while patients in the blank control group were not treated. Each course took 3 months, and patients received one or two courses. Lung CT scans were carried out after 3 and 6 months, and treatment efficacy was evaluated based on the reduction rate of the maximum diameter area of pulmonary nodules combined with the density and morphological changes.Results In total, 115 patients completed the study（77 patients in the experimental group and 38 patients in the blank control group）. The total clinical effective rates for the experimental group at 3 and 6 months were 51.95% and 49.02%, respectively, which were higher compared to 7.89% and 8.57%, respectively for the blank control group（P＜0.01）. The maximum diameter of solid pulmonary nodules in the experimental group decreased compared with the baseline value, while it increased in the blank control group.Conclusion Under the condition of limited traditional syndrome differentiation and treatment, the treatment of medium-risk solid pulmonary nodules based on overall pathogenesis state received certain clinical efficacy.

目的 基于Wnt/β-catenin通路探讨养阴益气方对肺纤维化的治疗作用,观察其对肺间质纤维化大鼠模型肺组织中Wnt/β-catenin通路相关指标表达影响.方法 选取36只SPF级雄性Wistar大鼠,按随机数字表法分为假手术组、模型组、阳性对照组、养阴益气方低、中、高剂量组,采用一次性气管内插管滴注博来霉素(Bleomycin,BLM)的方法造模;造模后第2天开始通过灌胃方式给予各组大鼠相应药物进行干预治疗.于第28天腹主动脉取血法处死全部大鼠,留取肺组织,行相关检测;通过HE和Masson染色方法进行病理检测,分别采用RT-PCR法和Western-blot法检测大鼠肺组织中Wnt3a、β-连环蛋白(β-catenin)、低密度脂蛋白受体相关蛋白(Lowdensitylipoprotein receptor-related protein,LRP)、Wnt抑制因子1(Wnt inhibitory factor 1,WIF1)、糖原合成酶激酶-3β(Glycogen synthase kinase-3β,GSK-3β)、I型胶原(Collagen I)的mRNA和蛋白表达情况.结果 养阴益气方明显减轻大鼠肺泡炎和纤维化的程度,下调肺纤维化大鼠肺组织中Wnt3a、β-catenin、GSK-3β、LRP、Collagen I的蛋白及基因表达,并上调WIF1表达,从而减轻肺纤维化程度,差异有统计学意义(P<0.05),尤以养阴益气方中、高剂量组效果明显.结论 养阴益气方可能通过抑制Wnt/β-catenin信号通路相关分子基因及蛋白表达抑制大鼠肺泡炎程度及肺纤维化发展.

三焦是包罗联系脏腑的膜系,内联脏腑微膜、外联肌肤筋骨关节,上下连接五脏六腑,为膜性四通管道,完成气机气化,促进水液运行,化生护卫精微.类风湿关节炎继发肺间质纤维化的中医病机为正气亏虚、三焦不利、痰瘀互结痹阻关节及肺微膜.初病感受风、寒、湿等外邪,蕴于筋骨关节,迁延日久化生痰浊瘀血,痹阻关节且内舍三焦膜性管道,流窜停滞肺微膜,发为肺间质纤维化.三焦"四通膜性管道"是关节痰瘀流窜肺脏的通路,三焦不利则加重痰浊瘀血停滞.临床治疗以"通、化、调"为原则疏利三焦,即选择理气活血祛风之通药、补肺温肾化气之化药,以调理脏腑状态,畅通三焦膜性管道,消散痹阻肺微膜之痰瘀浊邪.

新型冠状病毒奥密克戎感染常以发热为初始症状,疫毒从口鼻而入,首先犯肺,大多数患者发热1～3d热退后常见咳嗽;少数人发热持续4～5d以上,常出现病毒性肺炎.初起轻症时常表现为外寒内热证、湿热犯肺证;发展至重症肺炎时常见疫毒入肺证,湿热蕴肺、正虚痰瘀证;疫毒耗伤正气,恢复期以气阴亏虚为主.根据发热时间、热势、舌脉症状等辨证施治,以清热化湿解毒为主,肺炎期注意扶正化痰活血.

结缔组织病相关间质性肺病常涉及多脏腑、多系统病变,多累及肺、关节、肌肉和皮肤.三焦膜系理论认为三焦由人体脏腑包膜、间质和淋巴等构成,是水液运行、气机升降出入和气化的通道,可联络周身.认为三焦膜系是结缔组织病相关间质性肺病的核心病位,上焦膜系通过间质和胸膜连接肺,易于感邪和留邪,多种免疫疾病均易导致肺间质病变.据此提出肺肾亏虚是结缔组织病相关间质性肺病的内因,痰瘀阻滞是其病理产物;治疗当以疏利三焦为核心,结合不同兼证进行加减配伍.

特发性肺纤维化(IPF)是慢性、进展性、纤维化性的间质性肺疾病,其病因及发病机制尚未完全阐明,临床缺乏安全有效的治疗手段."状态医学"是姜良铎教授依据多年临床经验总结出的学术思想.姜教授提出从状态论治应从整体出发,不局限于中医的望闻问切,应全面认识、收集疾病相关信息,对其进行抽丝剥茧的分析.从状态论治IPF应把握其病机状态:IPF核心病机为肺脾肾亏虚,痰瘀深伏凝结肺络,因此补益肺脾肾、活血化痰、散结通络贯穿始终;依据患者就诊时的状态辨别其当前病机,采用清热、养阴等治法对证治疗,往往可获良效.

目的 观察从状态论治中危纯磨玻璃肺结节(pGGNs)的临床疗效与安全性.方法 将141例pGGNs患者随机分为治疗组92例及对照组49例.治疗组给予基础散结方结合辨中医状态加味处方口服,每日1剂,以3个月为1个疗程,治疗3个月后复查CT,临床判定为治愈、中危转为低危结节者、转而手术切除者无需进行第2个疗程治疗,其余患者完成第2个疗程的治疗.对照组患者不予任何治疗,仅于3、6个月时定期随访.两组患者均于入组时及入组3、6个月检查胸部CT,根据胸部CT所示肺结节最大径计算肺结节面积,于入组3、6个月根据肺结节面积减小率判定临床疗效,并进一步探讨治疗组入组6个月不同中医状态pGGNs患者的临床疗效差异;入组时及入组3、6个月分别计算Mayo风险概率.研究期间记录不良事件发生情况及检测安全性指标.结果 研究过程中治疗组脱落8例、对照组脱落7例,最终共完成126例观察,其中治疗组84例,对照组42例.入组3个月,治疗组临床疗效总有效率为46.15％(30/65),对照组为12.50％(4/32);入组6个月,治疗组总有效率为45.71％(32/70);对照组为10.00％(4/40).两个时间点治疗组临床疗效均优于对照组(P＜0.01).入组3、6个月治疗组结节面积较入组时均显著减小(P＜0.01),而对照组各时间点结节面积差异无统计学意义(P＞0.05).与本组入组时比较,治疗组患者入组3、6个月Mayo风险概率均显著减小(P＜0.01),而对照组入组6个月Mayo风险概率增加(P＜0.05).治疗组84例患者中气虚状态15例,阴虚状态7例,阳虚状态5例,气郁状态20例,湿热状态32例,无偏颇状态5例;不同中医状态患者入组6个月临床疗效总有效率分布差异有统计学意义(P＜0.05),两两比较气郁状态总有效率(13/20,65.00％)高于湿热状态总有效率(8/32,25.00％,P＜0.00833).两组患者入组后血常规、尿常规、肝功能、肾功能均未发生明显变化,未出现不良事件.结论 从状态论治中危纯磨玻璃肺结节能够有效减小肺结节面积,降低肺结节增长的恶性风险,且安全性较好.

肺癌是我国及世界上发病率和死亡率较高的恶性肿瘤之一,以外科手术根治性切除治疗为主,复发转移是肺癌患者治疗失败乃至死亡的重要原因之一,现代医学对其治疗以外科手术、放疗、化疗为主.三焦膜性管道论认为三焦是人体器官的包膜、淋巴、间质组织等组成的膜性四通管状通道,上下流通连接心肺等五脏六腑,内外流通连接卫表肌腠皮肤筋骨,为气与水液运行的通道,具有调控水液和气机运行、气化产生护卫精微的作用.本文基于三焦膜性管道论,认为三焦膜性管道为肺癌复发转移的通道,三焦郁滞促进癌毒停滞,癌毒随痰饮瘀血停滞于三焦膜性管道中运行布散内伏,通过三焦膜性管道流于全身各处,从而形成机体各处的转移灶,并总结其基本病机为三焦郁滞、正虚伏毒,治疗以疏利三焦、扶正抗癌为原则,重在"通、化、调","通"即通畅三焦气机,"化"即恢复三焦气化功能,"调"即调理脏腑气血、解毒抑癌,为中医学防治肺癌复发转移提供了新的思路与方法.

肺结节是肺部影像学的表现,患者缺少典型的呼吸系统症状,如咳嗽、咳痰、气喘等,在评价中医药治疗肺结节疗效时,无法使用以症状为主的中医证候评分评价体系,因此建立肺结节中医药临床疗效评价体系具有必要性和紧迫性.本文遵循国内外权威肺结节诊疗指南,在开展的大量临床研究实践基础上,总结提出了肺结节中医药临床疗效评价方法.本评价方法以总有效率为主要疗效指标,即综合考虑肺结节横截面积变化率和(或)直径变化、恶性征象变化,将疗效分为治愈、显效、有效、稳定、进展5个等级,总有效率(％)=(治愈例数+显效例数+有效例数)/总例数×100％;次要疗效指标包括平均直径变化、平均横截面积变化、危险度转化率、Mayo模型计算的恶性概率变化;以3、6个月为评价周期.建立以结节直径或横截面积变化为主的多维度疗效评价体系,有利于为中医药治疗肺结节的临床研究提供规范化、系统化及高循证级别的证据.

肺结节作为新兴的肺系疑难疾病,诊疗策略仍处于研究完善阶段,患者常无症状,传统中医辨证困难,胸部CT作为最常用的检查手段可延伸望诊.西医处理策略以定期随访为主,恶性者即手术切除,中医药在西医随访期干预意义重大.文章探讨肺结节的中医药诊疗策略,强调从大小、良恶性质、数目、危险因素等辨识结节,抓住肺结节气滞津停、痰瘀阻络的核心病机,从状态综合治疗,提高中医药诊治疗效,防止癌变发生.

目的:对孤立性肺结节良恶性预测模型进行系统评价,探讨孤立性肺结节恶性风险的独立危险因素,并对预测模型的效能进行评价和文献特征展示,以便查找具备优势的预测模型供临床选取.方法:检索CNKI、VIP、Wan-fang和Pubmed、Embase、Web of science等数据库,检索时间为自建库至2021年2月9日所有关于孤立性肺结节的良恶性预测模型,建模组为病理诊断或病理诊断联合随访的孤立性肺结节患者,由2位研究者对文献进行筛选,建立Excel表格进行分析.结果:共纳入文献27篇,包含27个建模公式,涉及独立危险因素29个,累计出现频次145次,其中出现次数≥2次的独立危险因素依次是:年龄、直径、分叶征、毛刺征、胸膜牵拉征、血管集束征、Cyfra21-1、肿瘤家族史、边界不清、空泡征、磨玻璃成分、吸烟史、肿瘤史、癌胚抗原、18 F-FDG摄取、SUVmax、边界清楚、空气支气管征、女性、神经元特异性烯醇化酶、男性、上叶,一共出现138次,占95.17％.常见的保护因素有钙化、边界清楚、边界光滑;纳入研究的方法学质量评价整体偏倚风险小,模型AUC值为0.701～0.979.结论:纳入的模型具有良好的预测效能,模型中包含的独立危险因素可帮助医护人员早期识别恶性肺结节高危人群,但模型的外推性尚未得到有效评价,后期建模或可从高频独立危险因素入手,建立更加完备的预测模型,扩大临床推广范围.

结节病是一种累及多脏器的免疫相关复杂疑难疾病,其病理学特征为非干酪样坏死性上皮样细胞肉芽肿.肺及胸部淋巴结最易受累,约占临床发病的90％,又称肺结节病.三焦膜系理论认为三焦由人体器官的包膜、淋巴和间质组织等构成,是气机升降出入和气化的场所,亦是水液运行的通道,可完成人体气、水液和护卫精微在周身的运行和布散.本课题组在临床实践中总结认为,肺结节病的病位主要在肺,基本病机是正气虚弱为本,痰瘀互结为标,三焦膜系郁滞、气化不利、痰瘀流窜为变.肺结节病在元气亏虚的基础上,出现三焦膜系气机、气化不利,导致出现痰瘀互结和脏腑功能受损,痰瘀阻滞三焦膜系,随膜系流窜至周身.治疗肺结节病的原则是疏利三焦、化痰散结、益气活血."通""化""调"是治疗的关键,"通"即通畅三焦,"化"即促进气化,"调"即调理气血.本课题组在临床中常用通化方治疗肺结节病.元气亏虚、三焦郁滞、痰瘀互结是肺结节病的核心,临床运用通化方可有效治疗肺结节病.

三甲复脉汤出自清代吴鞠通《温病条辨》,系治疗温病后期,热邪深入下焦,真阴耗伤,虚风内动之主方.姜良铎教授在临床上常应用此方思路加减治疗失眠症,为探求其疗效作用机制,笔者运用文献研究、经验总结等研究方法,从失眠病因病机、临床思路探讨等多个方面论证了其治疗失眠症的有效作用.分析结果显示,应用三甲复脉汤从调和营卫、调理脏腑、调畅神机3个方面治疗失眠症,能够起到滋补肝肾、潜阳熄风、镇惊安神的作用,临床中常能取得不错的疗效.

肺结节是近年来常见的肺系疑难疾病,因患者多无咳嗽、咳痰、喘息等肺部症状,识别相对困难,只能借助肺CT来诊断,现在影像学技术发展迅速,加之空气污染雾霾颗粒吸入、肥甘厚味酿湿生痰、焦虑压力阻滞气机等使得肺结节患者越来越多.肺结节有良、恶性之分,恶性肺结节多为肺癌的前期病变,值得重视,笔者通过查阅文献发现肺结节属于正虚痰瘀者居多,临床上从正虚痰瘀治疗入手往往取得良好疗效,此文从正虚痰瘀入手讨论肺结节的治疗,以期为肺结节的治疗提供一些借鉴.

总结姜良铎教授从通从毒论治肺结节的临床经验.认为肺结节属正虚气滞湿阻,痰瘀毒邪郁滞,局部积聚造成"不通"状态而成,"从通从毒论治"肺结节,是消除肺结节、抑制结节化毒癌变的有效方法.凡通调首先注重理气,一方面调畅胸中气机,另一方面疏解肝气、复肝疏泄之性,人体气机条畅,方能津液流通不滞,血行通畅;其次亦重视扶正补虚,尤应侧重补肺、肾、脾三脏;再次加强利湿化痰祛浊,活血散瘀,配以搜剔性强、通利经络的药物以通络散结,消除积聚.肺结节之解毒化积,常配以清热解毒化湿中药,其具有较强的抑毒散结的作用.

目的:应用生物信息学方法挖掘小细胞肺癌(small cell lung cancer,SCLC)的相关基因,探讨其发病机制,为SCLC诊断和治疗提供靶点.方法:从GEO(Gene Expression Omnibus)数据库中下载基因芯片数据集GSE43346和GSE6044,利用在线分析工具GEO2R筛选SCLC的差异表达基因(differentially expressed genes,DEGs).应用DAVID数据库进行GO和KEGG通路富集分析,利用STRING数据库和Cytoscape软件构建蛋白质相互作用网络和关键基因模块,筛选SCLC关键基因.运用UCSC和ONCOMINE数据库中的临床组织样本验证靶基因与SCLC的关系.结果:初筛出114个DEGs,富集分析发现差异基因在细胞分裂、细胞周期、有丝分裂、DNA复制等方面存在显著富集.共筛选出12个SCLC靶基因,经临床SCLC组织样本验证关键基因在SCLC组织中存在显著高表达.其中FBXO5、NCAPG、GINS2、GMNN、MCM6、ESPL1、MCM2、NDC80、BUB1 B、CCNB2基因可能是SCLC分子发病机制的新靶点.结论:通过生物信息学筛选出10个与SCLC相关的新靶点,表明其可能是未来研究SCLC发病机制、临床诊断和治疗的重要靶基因.

Background: Immune checkpoint inhibitors (ICIs) have previously been reported to have a promising potential in terms of the improvement of outcomes in non–small cell lung cancer (NSCLC). Fatal adverse events (FAEs) of ICIs are relatively uncommon, and the incidence and risk in NSCLC remain unclear. In the present study, we conducted a systematic review and meta-analysis to evaluate the risk of FAEs in NSCLC patients administered with ICIs. Methods: Potentially relevant studies were identified in PubMed, EMBASE, and Cochrane library database from inception to September 16, 2020. The systematic review and meta-analysis included randomized controlled trials that reported treatment-related FAEs in NSCLC. The pooled incidence and risk ratios (RRs) were calculated to evaluate prospective risk. Results: Twenty clinical trials that included a total of 13,483 patients were selected for the meta-analysis. The overall incidence of FAEs was 0.65% [95% confidence interval (CI) = 0.31–1.07, I2 = 50.2%] in ICI monotherapy, 1.17% (95% CI = 0.74–1.69, I2 = 56.3%) in chemotherapy, and 2.01% (95% CI = 1.42–2.69, I2 = 5.9%) in the combination therapy (ICI and chemotherapy). ICI monotherapy was associated with lower incidence of FAEs caused by blood system disorders (RR = 0.23, 95% CI = 0.07–0.73, P = 0.013, I2 = 0%) and infectious diseases (RR = 0.29, 95% CI = 0.13–0.63, P = 0.002, I2 = 0%). The incidence of pneumonitis significantly increased in immunotherapy (RR = 5.72, 95% CI = 1.14–28.80, P = 0.03, I2 = 0%). Conclusions: The results of the present study demonstrate that ICI monotherapy decreases the risk of FAEs, whereas the combined regimens with chemotherapy have the opposite tendency as compared to conventional chemotherapy. While the patients who received chemotherapy suffered the risks of death mainly from myelosuppression and infection, those who received immunotherapy were mainly threatened by immune-related pneumonitis.