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An international multicentre study of SwiTching from Intravenous to subcutaneous inflixiMab and vEdolizumab in inflammatory bowel diseases: The TIME study 一项关于炎症性肠病患者从静脉注射到皮下注射英夫利珠单抗和维妥珠单抗的国际多中心研究：TIME 研究。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-07-09 DOI: 10.1111/eci.14283
Ferdinando D'Amico, Luca Massimino, Giulia Palmieri, Arianna Dal Buono, Roberto Gabbiadini, Benedicte Caron, Paula Moreira, Isabel Silva, Maia Bosca-Watts, Tommaso Innocenti, Gabriele Dragoni, Cristina Bezzio, Alessandra Zilli, Federica Furfaro, Simone Saibeni, María Chaparro, María José García, George Michalopoulos, Nikos Viazis, Gerassimos J. Mantzaris, Pierre Ellul, Javier P. Gisbert, Fernando Magro, Laurent Peyrin-Biroulet, Alessandro Armuzzi, Federica Ungaro, Silvio Danese, Gionata Fiorino, Mariangela Allocca

Background and Aims

Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel diseases (IBDs). Our aim was to evaluate the effectiveness of switching from intravenous (IV) to SC formulations of IFX and VDZ in IBDs.

Methods

This multicentre, retrospective study collected data of adult patients with Crohn's disease (CD) or ulcerative colitis (UC) switched to SC IFX or VDZ. The primary endpoint was clinical remission at 12 months stratified based on timing of switch. A composite endpoint consisting of therapy discontinuation, reverse-switch, need for steroids, and drug optimization was evaluated. A multivariate analysis investigated the association between patients' characteristics and outcomes.

Results

Two hundred and thirty-one patients (59% UC, 53% male, mean age 44 ± 15 years, 68% IFX) from 13 centres were included. The switch occurred at Week 6 in a third of cases (36%). Median time to switch was 13 months. Most patients switched to SC IFX and VDZ were in clinical remission at 3 (87% and 77%), 6 (86% and 83%) and 12 (63% and 60%) months. In the multivariate analysis, there was no difference in clinical remission rate at 12 months; however, patients switched at Week 6 had a higher rate of experiencing any therapeutic changes at 3 (false discovery rate (FDR) = .002), 6 (FDR <1 × 10−10) or 12 months (FDR = .08). Clinical disease activity at baseline (only in UC) (FDR = .07) and previous exposure to biologics (FDR = .001) were risk factors for composite endpoint at 6 and 12 months.

Conclusion

SC IFX and VDZ are effective in daily clinical practice in IBD patients. Switching patients in remission reduces the risk of negative outcomes.

背景和目的：英夫利昔单抗（IFX）和维妥珠单抗（VDZ）的皮下注射制剂已被批准用于治疗炎症性肠病（IBD）。我们的目的是评估 IFX 和 VDZ 从静脉注射制剂转为 SC 制剂治疗 IBD 的有效性：这项多中心回顾性研究收集了改用皮下注射 IFX 或 VDZ 的克罗恩病（CD）或溃疡性结肠炎（UC）成年患者的数据。主要终点是12个月时的临床缓解，根据转换时间进行分层。评估的复合终点包括治疗中断、反向转换、类固醇需求和药物优化。一项多变量分析调查了患者特征与治疗结果之间的关系：13个中心的231名患者（59%为UC，53%为男性，平均年龄为44±15岁，68%为IFX）被纳入研究。三分之一的病例（36%）在第 6 周进行了换药。中位转换时间为 13 个月。大多数转用 SC IFX 和 VDZ 的患者在 3 个月（87% 和 77%）、6 个月（86% 和 83%）和 12 个月（63% 和 60%）时临床症状缓解。在多变量分析中，12 个月时的临床缓解率没有差异；但是，在第 6 周时换药的患者在 3 个月（假发现率 (FDR) = .002）、6 个月（FDR -10）或 12 个月（FDR = .08）时出现任何治疗变化的比率较高。基线时的临床疾病活动性（仅在 UC 中）（FDR = .07）和既往接触过生物制剂（FDR = .001）是 6 个月和 12 个月时出现复合终点的风险因素：结论：SC IFX和VDZ在IBD患者的日常临床实践中是有效的。结论：SC IFX 和 VDZ 在 IBD 患者的日常临床实践中非常有效。
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引用次数: 0
The glucagon-like peptide-1 receptor agonist semaglutide in diabetic kidney disease: A new kid on the block to afford maximal kidney protection 胰高血糖素样肽-1 受体激动剂 semaglutide 在糖尿病肾病中的应用：为肾脏提供最大保护的新生力量。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-07-09 DOI: 10.1111/eci.14284
Panagiotis I. Georgianos, Konstantinos Leivaditis, Vassilios Liakopoulos
<p>Chronic kidney disease (CKD) is the most common complication of type 2 diabetes (T2D).<span><sup>1</sup></span> The co-existence of CKD and T2D is associated with a substantially higher risk for adverse cardiovascular outcomes and faster deterioration of kidney function.<span><sup>2</sup></span> For almost two decades, the only available pharmacological interventions to mitigate this excess cardiorenal risk included the optimization of blood glucose levels towards an individualized glycaemic target, the adequate blood pressure control and the use of an agent blocking the renin–angiotensin system (RAS) at maximum or maximally tolerated doses.<span><sup>3</sup></span> Fortunately, this disappointing picture has been modified after the discovery of novel therapies that afford additive cardiorenal protective benefits.<span><sup>3</sup></span> In a triad of landmark trials conducted specifically in CKD patients who were already treated with a RAS blocker, sodium-glucose co-transporter type 2 (SGLT-2) inhibitors provoked an impressive placebo-subtracted reduction in the risk of kidney failure and death from kidney or cardiovascular causes.<span><sup>4</sup></span> Similarly, in a large phase 3 clinical trial programme involving 13,026 patients with T2D and a broad spectrum of CKD, the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone improved the composite kidney and cardiovascular outcomes relative to placebo.<span><sup>5</sup></span> Once again, these additive effects were demonstrated in patients receiving optimized background therapy with maximally tolerated doses of a RAS blocker before randomization.<span><sup>5</sup></span> On this scientific basis, both SGLT-2 inhibitors and finerenone have been included as recommended pharmacological interventions for patients with CKD associated with T2D in recently released guidelines.<span><sup>6, 7</sup></span> However, the residual cardiorenal risk of these patients remains an unresolved issue, generating the need for additional effective therapies.</p><p>In this Commentary, we discuss the kidney protective effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with diabetic kidney disease, providing a critical evaluation of the results of the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial.<span><sup>8, 9</sup></span></p><p>GLP-1RAs are established and guideline-directed therapies for the improvement of glycaemic control and weight loss in patients with T2D.<span><sup>6, 7</sup></span> Some agents that belong to this novel antidiabetic drug class also mitigate the risk for major adverse cardiovascular events in patients with T2D and established cardiovascular disease or in people with T2D and multiple cardiovascular risk factors.<span><sup>6, 7</sup></span> However, until recently, the potential kidney protective effects of GLP-1RAs were based mainly on indirect evidence from secondary exploratory analyses of cardiovascular outcome or glycaemic
11 综上所述，这些令人鼓舞的初步结果为 FLOW 研究的设计提供了依据。FLOW 研究是一项专门的 3 期临床试验，旨在全面阐明 GLP-1RA semaglutide 与安慰剂相比，对肾损伤进展风险较高的慢性肾脏病和 T2D 患者的肾脏保护作用。在 FLOW 试验中，3533 名 T2D 和白蛋白尿 CKD 患者（定义为 eGFR 为 50-75 mL/min/1.73 m2 和 UACR 为 300-5000 mg/g，或 eGFR 为 25 至 50 mL/min/1.73 m2 和 UACR 为 100-5000 mg/g）按 1:1 的比例随机接受每周 1 克剂量的皮下注射塞马鲁肽或匹配安慰剂的双盲治疗（表 1）。8 根据这些预设的选择标准，参加试验的患者确实存在慢性肾功能衰竭恶化的风险（基线 eGFR：47.0 ± 15.2 mL/min/1.73 m2；基线 UACR：567.6 mg/g）。几乎所有患者在随机分组前都接受了 RAS 阻断剂的标准治疗。与之前的 SGLT-2 抑制剂试验类似，FLOW 试验也因积极治疗的疗效而提前终止。在 3.4 年的中位随访期中，塞马鲁肽使主要结果（即 eGFR 从基线持续下降 50%、出现 ESKD 或因肾脏和心血管原因死亡的综合结果）的安慰剂减量降低了 24%（HR：.76；95% CI：.66-.88）。心血管和生存方面的益处也得到了证实。与安慰剂相比，赛马鲁肽将主要不良心血管事件风险降低了 18%（HR：.82；95% CI：.68-.98），将全因死亡风险降低了 20%（HR：.80；95% CI：.67-.95）。8 这些有力的临床试验数据直接支持了semaglutide 在伴有 T2D 的白蛋白尿 CKD 高危患者中的治疗作用。例如，1832 例患者（51.8%）正在接受二甲双胍的背景治疗。在二甲双胍使用者（HR：.71；95% CI：.57-.88）和非使用者（HR：.80；95% CI：.66-.97）8 中，semaglutide 与安慰剂相比对主要综合结果的治疗效果相似。同样，接受 SGLT-2 抑制剂背景治疗的患者（HR：1.07；95% CI：.67-1.67）与未接受 SGLT-2 抑制剂背景治疗的患者（HR：.73；95% CI：.63-.85）相比，治疗效果没有明显改善，8 这表明当塞马鲁肽与其他指导性疗法联合使用时，可能会产生协同效应。然而，必须指出的是，这些数据的事后性质和有限的统计能力排除了建立直接和因果风险关联的机会。GLP-1RAs 通过与 GLP-1 受体结合发挥降糖作用，从而促进葡萄糖依赖性胰岛素部分、延长胃排空和降低食欲。目前尚不完全清楚，在糖尿病肾脏疾病中，塞马鲁肽对肾脏具有保护作用的机制是什么。心血管结果试验的中介分析支持这样一种观点，即间接作用，如改善血糖控制、减轻体重和降低办公室血压水平，只能部分解释 GLP-1RAs 提供的心肾保护作用。因此，根据临床前和生物标志物数据推测，GLP-1RAs 可直接抑制糖尿病肾病进展过程中的致病机制，如常驻单核吞噬细胞的激活、非常驻炎症细胞对肾脏的浸润以及促炎症细胞因子和粘附分子的表达。目前正在进行的 REMODEL（塞马鲁肽在 2 型糖尿病和慢性肾病患者中的肾脏作用模式）研究（NCT04865770）正在研究 GLP-1RA 塞马鲁肽保护肾脏的机制背景。这项3期临床试验计划招募105名患有白蛋白尿性慢性肾脏病并已接受最大标记剂量或耐受剂量RAS抑制剂治疗的2型糖尿病患者。患者将被随机分配接受皮下注射塞马鲁肽（1.0 毫克，每周一次）或安慰剂治疗，随访期为 52 周。 REMODEL 试验的主要结果是通过磁共振成像评估肾脏氧合、炎症和肾脏整体灌注变化的组间差异。还将对部分患者进行肾活检，通过单核 RNA 测序研究基因表达的变化和形态参数的变化。最后，还将收集血液和尿液样本，以评估肾功能和肾损伤的生物标志物。总之，尽管 SGLT-2 抑制剂和非甾体类 MRA 非格列奈酮4、5 等新疗法改善了肾脏和心血管预后，但糖尿病肾病患者仍会发展为肾衰竭，并因心血管事件而过早死亡。主要来自心血管结果和血糖控制试验二次分析的间接证据表明，GLP-1RAs 可能对肾脏有保护作用。10-12 然而，目前还没有专门针对 CKD 和 T2D 肾病进展高风险患者进行的大规模 3 期临床试验。最近发表的 FLOW 试验填补了这一重要的科学空白，提供了直接证据表明，塞马鲁肽对伴有白蛋白尿的 CKD 和 T2D 患者的肾脏、心血管和存活率有很大益处，同时还具有安全治疗的良好副作用：文献检索：P.I.G.；手稿初稿起草：P.I.G：文献检索：P.I.G.；手稿初稿的起草：P.I.G.；初稿的审阅和修改：K.L. 和 V.L：K.L. 和 V.L.；指导：V.L.这项工作没有得到任何来源的支持，是作者们的原创性工作。作者们没有与这项工作相关的利益冲突需要披露。
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引用次数: 0
The association between bilirubin concentrations and inflammatory bowel disease: Insights from a systematic review and meta-analysis 胆红素浓度与炎症性肠病之间的关系：系统回顾和荟萃分析的启示。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-07-05 DOI: 10.1111/eci.14281
Stefano Zoroddu, Biagio Di Lorenzo, Panagiotis Paliogiannis, Arduino A. Mangoni, Ciriaco Carru, Angelo Zinellu

Background

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), poses a significant challenge to health care systems because of its chronic nature and increasing global prevalence. Effective management of IBD requires accurate diagnostic tools and biomarkers. This systematic review and meta-analysis aimed to evaluate the relationship between bilirubin concentrations and IBD activity and outcomes.

Methods

A comprehensive search of electronic databases identified 11 studies that included 2606 subjects with IBD and 3607 healthy controls.

Results

Bilirubin concentrations were significantly lower in subjects with IBD when compared to controls (SMD = −0.96, 95% CI −1.21 to −0.70; p < .001). Although substantial heterogeneity was observed, sensitivity analysis confirmed the robustness of the results. Publication bias was detected, but subgroup analyses did not significantly alter the results. Meta-regression showed that age was a significant factor influencing the association between bilirubin concentrations and IBD. Subgroup analyses showed a more pronounced reduction in bilirubin concentrations in subjects with CD than those with UC.

Conclusion

This study supports the potential utility of bilirubin as a biomarker in IBD, emphasizing the need for further research to validate its clinical significance.

背景：炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），由于其慢性性质和全球发病率不断上升，给医疗保健系统带来了巨大挑战。有效管理 IBD 需要准确的诊断工具和生物标志物。本系统综述和荟萃分析旨在评估胆红素浓度与 IBD 活动和结果之间的关系：方法：通过对电子数据库的全面搜索，确定了 11 项研究，其中包括 2606 名 IBD 患者和 3607 名健康对照者：结果：与对照组相比，IBD受试者的胆红素浓度明显降低（SMD = -0.96，95% CI -1.21 to -0.70；P 结论：该研究证实了胆红素浓度的潜在作用：本研究支持胆红素作为 IBD 生物标记物的潜在作用，强调了进一步研究验证其临床意义的必要性。
{"title":"The association between bilirubin concentrations and inflammatory bowel disease: Insights from a systematic review and meta-analysis","authors":"Stefano Zoroddu,&nbsp;Biagio Di Lorenzo,&nbsp;Panagiotis Paliogiannis,&nbsp;Arduino A. Mangoni,&nbsp;Ciriaco Carru,&nbsp;Angelo Zinellu","doi":"10.1111/eci.14281","DOIUrl":"10.1111/eci.14281","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), poses a significant challenge to health care systems because of its chronic nature and increasing global prevalence. Effective management of IBD requires accurate diagnostic tools and biomarkers. This systematic review and meta-analysis aimed to evaluate the relationship between bilirubin concentrations and IBD activity and outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A comprehensive search of electronic databases identified 11 studies that included 2606 subjects with IBD and 3607 healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Bilirubin concentrations were significantly lower in subjects with IBD when compared to controls (SMD = −0.96, 95% CI −1.21 to −0.70; <i>p</i> &lt; .001). Although substantial heterogeneity was observed, sensitivity analysis confirmed the robustness of the results. Publication bias was detected, but subgroup analyses did not significantly alter the results. Meta-regression showed that age was a significant factor influencing the association between bilirubin concentrations and IBD. Subgroup analyses showed a more pronounced reduction in bilirubin concentrations in subjects with CD than those with UC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study supports the potential utility of bilirubin as a biomarker in IBD, emphasizing the need for further research to validate its clinical significance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Which is the best glomerular filtration marker: Creatinine, cystatin C or both? 哪种是最好的肾小球滤过标志物？肌酐、胱抑素 C 还是两者都有？
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-07-01 DOI: 10.1111/eci.14278
Thomas Stehlé, Pierre Delanaye

Background

The glomerular filtration rate (GFR) is estimated by the serum or plasma concentration of creatinine and/or cystatin C using equations that include demographic data. The equations worldwide most widely used are those of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) consortium and updated in 2021 to remove the Afro-American racial correction factor. In 2021 and then in 2023, the European Kidney Function Consortium also developed equations based on creatinine and cystatin C, usable across the full age spectrum, and constructed by including the Q value (i.e. the median creatinine or cystatin C in healthy men and women, which is customizable for specific populations).

Methods

The aim of this narrative review is to examine the strengths and weaknesses of each biomarker.

Results

Both biomarkers have non-GFR determinants, namely muscle mass, protein intake and tubular secretion for creatinine; dysthyroidism and systemic corticosteroids for cystatin C, as well as other more debated determinants (diabetes, obesity, proteinuria, inflammatory syndrome). These non-GFR determinants are the reason why no equation based on a single endogenous biomarker has an accuracy within 30% greater than 90% over the entire age spectrum (in at least one patient in 10, estimated GFR is at least 30% higher or at least 30% lower than the measured GFR).

Conclusion

Equations combining the two biomarkers provide a better estimate of GFR, particularly in the subgroup of patients whose estimates based on each of the biomarkers are highly discordant. These patients must also be identified as being at increased risk of morbidity, particularly cardiovascular, and mortality.

背景：肾小球滤过率（GFR）是根据血清或血浆中肌酐和/或胱抑素 C 的浓度，利用包含人口统计学数据的公式估算得出的。全球最广泛使用的公式是慢性肾脏病流行病学协作组（CKD-EPI）的公式，并在 2021 年进行了更新，删除了非裔美国人种族校正因子。2021 年和 2023 年，欧洲肾功能联盟也开发了基于肌酐和胱抑素 C 的方程，适用于所有年龄段，并通过加入 Q 值（即健康男性和女性的肌酐或胱抑素 C 中位数，可为特定人群定制）来构建：本综述旨在研究每种生物标志物的优缺点：结果：这两种生物标志物都有非基因FR决定因素，即肌酐的肌肉质量、蛋白质摄入量和肾小管分泌量；胱抑素C的甲状腺功能减退症和全身性皮质类固醇，以及其他更有争议的决定因素（糖尿病、肥胖、蛋白尿、炎症综合征）。这些非肾小球滤过率决定因素是导致基于单一内源性生物标志物的方程在整个年龄段的准确率都不能超过 90%（每 10 个患者中至少有 1 个患者的估测肾小球滤过率比测量的肾小球滤过率高至少 30%或低至少 30%）的原因：结论：结合两种生物标记物的等式能更好地估算出 GFR，尤其是在根据每种生物标记物估算的结果都很不一致的亚组患者中。这些患者的发病（尤其是心血管疾病）和死亡风险也必须加以识别。
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引用次数: 0
Stroke outcomes following cardiac and aortic surgery are improved by the involvement of a stroke team 心脏和主动脉手术后的卒中预后可通过卒中团队的参与得到改善。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-29 DOI: 10.1111/eci.14275
Amer Harky, Vanessa Jane Chow, Calum Voller, Kartik Goyal, Matthew Shaw, Anurodh Bhawnani, Ayman Kenawy, Ian Wilson, Gregory Y. H. Lip, Mark Field, Manoj Kuduvalli

Objectives

Post-cardiac and aortic surgery stroke is often underreported. We detail our single-centre experience the following introduction of comprehensive consultant-led daily stroke service, to demonstrate the efficacy of a stroke team in recovery from stroke following cardiac and aortic surgeries.

Methods

This retrospective, single-centre observational cohort study analysed consecutive patients undergoing cardiac and aortic surgery at our institution from August 2014 to December 2020. Main outcomes included stroke rate, predictors of stroke, and neurological deficit resolution or persistence at discharge and clinic follow-up.

Results

A total of 12,135 procedures were carried out in the reference period. Among these, 436 (3.6%) suffered a stroke. Overall survival to discharge and follow-up were 86.0% and 84.0% respectively. Independent risk factors for post-operative stroke included advanced age (OR 1.033, 95% CI [1.023, 1.044], p < .001), female sex (OR 1.491, 95% [1.212, 1.827], p < .001), history of previous cardiac surgeries (OR 1.670, 95% CI [1.239, 2.218], p < .001), simultaneous coronary artery bypass graft + valve procedures (OR 1.825, 95% CI [1.382, 2.382], p < .001) and CPB time longer than 240 min (OR 3.384, 95% CI [2.413, 4.705], p < .001). Stroke patients managed by the multidisciplinary team demonstrated significantly higher rates of survival at discharge (87.3% vs. 61.9%, p = .001).

Conclusions

Perioperative stroke can be debilitating immediately long term. The involvement of specialist stroke teams plays a key role in reducing the long-term burden and mortality of this condition.

目的：心脏手术和主动脉手术后中风的报道往往不足。我们详细介绍了我们单中心在引入顾问主导的全面日常卒中服务后的经验，以证明卒中团队在心脏和主动脉手术后卒中恢复中的有效性：这项回顾性、单中心观察性队列研究分析了 2014 年 8 月至 2020 年 12 月期间在我院接受心脏和主动脉手术的连续患者。主要结果包括卒中率、卒中的预测因素以及出院和门诊随访时神经功能缺损的缓解或持续情况：结果：参照期内共进行了 12 135 例手术。结果：参照期内共进行了 12 135 例手术，其中 436 例（3.6%）发生了中风。出院和随访的总生存率分别为 86.0% 和 84.0%。术后中风的独立风险因素包括高龄（OR 1.033，95% CI [1.023，1.044]，P 结论：术后中风可能会对患者的身体造成损害：围手术期中风可能会立即导致长期衰弱。卒中专科团队的参与对减少这种疾病的长期负担和死亡率起着关键作用。
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引用次数: 0
Association of MASLD with the risk of extrahepatic cancers: A systematic review and meta-analysis of 18 cohort studies MASLD与肝外癌症风险的关系：18项队列研究的系统回顾和荟萃分析。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-28 DOI: 10.1111/eci.14276
Ben-Gang Zhou, Xin Jiang, Qiang She, Yan-Bing Ding

Background

Numerous recent studies have explored the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of various extrahepatic cancers. However, the conclusions were inconclusive. The aim of this study was to clarify this relationship by conducting a robust meta-analysis.

Methods

Systematic searches were conducted on PubMed, Embase and Web of Science databases to identify relevant cohort studies published prior to February 2024. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were combined using a random-effects model in this meta-analysis.

Results

Eighteen cohort studies (approximately 16.7 million participants) were finally included in this meta-analysis. MASLD was linked to a higher risk of extrahepatic cancers, such as gastric (n = 10, HR = 1.47, 95% CI: 1.07–2.01), colorectal (n = 13, HR = 1.33, 95% CI: 1.16–1.53), pancreatic (n = 8, HR = 1.41, 95% CI: 1.11–1.79), biliary tract (n = 5, HR = 1.27, 95% CI: 1.18–1.37), thyroid (n = 6, HR = 1.46, 95% CI: 1.02–2.09), urinary system (n = 10, HR = 1.45, 95% CI: 1.25–1.69), breast (n = 11, HR = 1.17, 95% CI: 1.08–1.26) and female genital organ cancers (n = 10, HR = 1.36, 95% CI: 1.11–1.66). However, there was no statistically significant association between MASLD and the risk of head and neck (n = 6, HR = 1.03, 95% CI: 99–1.07), oesophageal (n = 9, HR = 1.26, 95% CI: 0.86–1.86), lung (n = 9, HR = 1.01, 95% CI: 0.92–1.10), prostate (n = 9, HR = 1.06, 95% CI: 0.94–1.19) or small intestine cancer (n = 2, HR = 1.75, 95% CI: 1.00–3.06).

Conclusions

This latest large-scale meta-analysis indicated that MASLD was associated with an increased risk of various extrahepatic cancers, such as gastric, colorectal, pancreatic, biliary duct, thyroid, urinary system, breast, skin and female genital cancers. Further research is needed to investigate the mechanisms underlying these associations.

背景：最近有许多研究探讨了代谢功能障碍相关性脂肪性肝病（MASLD）与各种肝外癌症风险之间的关系。然而，结论并不明确。本研究旨在通过进行可靠的荟萃分析来澄清这种关系：在 PubMed、Embase 和 Web of Science 数据库中进行系统检索，以确定 2024 年 2 月之前发表的相关队列研究。荟萃分析中使用随机效应模型合并了危险比（HRs）及其相应的 95% 置信区间（95% CIs）：本次荟萃分析最终纳入了18项队列研究（约1670万参与者）。MASLD与较高的肝外癌症风险有关，如胃癌（n = 10，HR = 1.47，95% CI：1.07-2.01）、结直肠癌（n = 13，HR = 1.33，95% CI：1.16-1.53）、胰腺癌（n = 8，HR = 1.41，95% CI：1.11-1.79）、胆道癌（n = 5，HR = 1.27，95% CI：1.18-1.37）、甲状腺癌（n = 6，HR = 1.46，95% CI：1.02-2.09）、泌尿系统癌症（n = 10，HR = 1.45，95% CI：1.25-1.69）、乳腺癌（n = 11，HR = 1.17，95% CI：1.08-1.26）和女性生殖器官癌症（n = 10，HR = 1.36，95% CI：1.11-1.66）。然而，MASLD与头颈部癌症（n = 6，HR = 1.03，95% CI：99-1.07）、食道癌（n = 9，HR = 1.26，95% CI：0.86-1.86）、肺癌（n = 9，HR = 1.01，95% CI：0.92-1.10）、前列腺癌（n = 9，HR = 1.06，95% CI：0.94-1.19）或小肠癌（n = 2，HR = 1.75，95% CI：1.00-3.06）：这项最新的大规模荟萃分析表明，MASLD 与罹患胃癌、结直肠癌、胰腺癌、胆管癌、甲状腺癌、泌尿系统癌、乳腺癌、皮肤癌和女性生殖器癌等各种肝外癌症的风险增加有关。需要进一步研究这些关联的机制。
{"title":"Association of MASLD with the risk of extrahepatic cancers: A systematic review and meta-analysis of 18 cohort studies","authors":"Ben-Gang Zhou,&nbsp;Xin Jiang,&nbsp;Qiang She,&nbsp;Yan-Bing Ding","doi":"10.1111/eci.14276","DOIUrl":"10.1111/eci.14276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Numerous recent studies have explored the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of various extrahepatic cancers. However, the conclusions were inconclusive. The aim of this study was to clarify this relationship by conducting a robust meta-analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Systematic searches were conducted on PubMed, Embase and Web of Science databases to identify relevant cohort studies published prior to February 2024. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were combined using a random-effects model in this meta-analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eighteen cohort studies (approximately 16.7 million participants) were finally included in this meta-analysis. MASLD was linked to a higher risk of extrahepatic cancers, such as gastric (<i>n</i> = 10, HR = 1.47, 95% CI: 1.07–2.01), colorectal (<i>n</i> = 13, HR = 1.33, 95% CI: 1.16–1.53), pancreatic (<i>n</i> = 8, HR = 1.41, 95% CI: 1.11–1.79), biliary tract (<i>n</i> = 5, HR = 1.27, 95% CI: 1.18–1.37), thyroid (<i>n</i> = 6, HR = 1.46, 95% CI: 1.02–2.09), urinary system (<i>n</i> = 10, HR = 1.45, 95% CI: 1.25–1.69), breast (<i>n</i> = 11, HR = 1.17, 95% CI: 1.08–1.26) and female genital organ cancers (<i>n</i> = 10, HR = 1.36, 95% CI: 1.11–1.66). However, there was no statistically significant association between MASLD and the risk of head and neck (<i>n</i> = 6, HR = 1.03, 95% CI: 99–1.07), oesophageal (<i>n</i> = 9, HR = 1.26, 95% CI: 0.86–1.86), lung (<i>n</i> = 9, HR = 1.01, 95% CI: 0.92–1.10), prostate (<i>n</i> = 9, HR = 1.06, 95% CI: 0.94–1.19) or small intestine cancer (<i>n</i> = 2, HR = 1.75, 95% CI: 1.00–3.06).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This latest large-scale meta-analysis indicated that MASLD was associated with an increased risk of various extrahepatic cancers, such as gastric, colorectal, pancreatic, biliary duct, thyroid, urinary system, breast, skin and female genital cancers. Further research is needed to investigate the mechanisms underlying these associations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction-associated steatotic liver disease 色氨酸通路的代谢谱分析：对肥胖症和代谢功能障碍相关脂肪肝的影响。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-28 DOI: 10.1111/eci.14279
Carmen Arto, Elena Cristina Rusu, Helena Clavero-Mestres, Andrea Barrientos-Riosalido, Laia Bertran, Razieh Mahmoudian, Carmen Aguilar, David Riesco, Javier Ugarte Chicote, David Parada, Salomé Martínez, Fàtima Sabench, Cristóbal Richart, Teresa Auguet

Background and Aims

The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD.

Materials and Methods

We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO).

Results

Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577–39.823) μM of tryptophan in NL subjects; 41.522 (38.803–45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS.

Conclusions

We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.

背景和目的：肥胖症的增加凸显了改进治疗策略的必要性，尤其是在解决代谢功能障碍相关性脂肪性肝病（MASLD）方面。我们的目的是评估色氨酸代谢途径在肥胖症发病机制中以及在 MASLD 不同组织学阶段中的作用：我们使用超高效液相色谱法量化了犬尿宁、吲哚和血清素途径中 15 种色氨酸相关代谢物的循环水平。我们对一组 76 名受试者进行了分析，其中包括 18 名体重正常的受试者和 58 名病态肥胖的受试者，最后这些受试者被细分为正常肝脏（NL）、单纯性脂肪变性（SS）和代谢功能障碍相关性脂肪性肝炎（MASH）。然后，我们对肝脏 IDO-1 和炔烃-3-单加氧酶（KMO）进行了基因表达分析：结果：肥胖症的主要研究结果显示了一种独特的代谢特征，其特点是不同的犬尿氨酸相关代谢物浓度升高，吲哚-3-乙酸和吲哚-3-丙酸含量降低，血清素通路发生改变。色氨酸水平升高与 MASLD 的存在有关（NL 受试者的色氨酸水平为 37.659（32.577-39.823）μM；MASLD 患者的色氨酸水平为 41.522（38.803-45.276）μM）。总体而言，通路通量显示，在 SS 受试者中，色氨酸通过血清素通路被诱导分解，而在 MASH 患者中，色氨酸通过犬尿氨酸通路被诱导分解。我们发现，与 SS 相比，NL 中 IDO-1 和 KMO 的肝脏表达量减少：我们在肥胖症中发现了一个独特的代谢特征，其特点是色氨酸分解代谢途径的变化，可通过代谢物谱的改变来辨别。我们观察到色氨酸代谢通路在 MASLD 中发生了特定阶段的变化，这凸显了针对这些通路进行治疗干预的潜在作用。
{"title":"Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction-associated steatotic liver disease","authors":"Carmen Arto,&nbsp;Elena Cristina Rusu,&nbsp;Helena Clavero-Mestres,&nbsp;Andrea Barrientos-Riosalido,&nbsp;Laia Bertran,&nbsp;Razieh Mahmoudian,&nbsp;Carmen Aguilar,&nbsp;David Riesco,&nbsp;Javier Ugarte Chicote,&nbsp;David Parada,&nbsp;Salomé Martínez,&nbsp;Fàtima Sabench,&nbsp;Cristóbal Richart,&nbsp;Teresa Auguet","doi":"10.1111/eci.14279","DOIUrl":"10.1111/eci.14279","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577–39.823) μM of tryptophan in NL subjects; 41.522 (38.803–45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"54 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/eci.14279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Omega-3 polyunsaturated fatty acids and pulmonary arterial hypertension: Insights and perspectives 欧米伽-3 多不饱和脂肪酸与肺动脉高压：见解与展望。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-28 DOI: 10.1111/eci.14277
Marika Massaro, Stefano Quarta, Nadia Calabriso, Maria Annunziata Carluccio, Egeria Scoditti, Peter Mancuso, Raffaele De Caterina, Rosalinda Madonna

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder that affects the pulmonary vasculature. Although recent developments in pharmacotherapy have extended the life expectancy of PAH patients, their 5-year survival remains unacceptably low, underscoring the need for multitarget and more comprehensive approaches to managing the disease. This should incorporate not only medical, but also lifestyle interventions, including dietary changes and the use of nutraceutical support. Among these strategies, n-3 polyunsaturated fatty acids (n-3 PUFAs) are emerging as promising agents able to counteract the inflammatory component of PAH. In this narrative review, we aim at analysing the preclinical evidence for the impact of n-3 PUFAs on the pathogenesis and the course of PAH. Although evidence for the role of n-3 PUFAs deficiencies in the development and progression of PAH in humans is limited, preclinical studies suggest that these dietary components may influence several aspects of the pathobiology of PAH. Further clinical research should test the efficacy of n-3 PUFAs on top of approved clinical management. These studies will provide evidence on whether n-3 PUFAs can genuinely serve as a valuable tool to enhance the efficacy of pharmacotherapy in the treatment of PAH.

肺动脉高压（PAH）是一种影响肺血管的罕见渐进性疾病。虽然药物治疗的最新进展延长了 PAH 患者的预期寿命，但他们的 5 年存活率仍然低得令人无法接受，这突出表明需要采取多目标和更全面的方法来控制这种疾病。这不仅包括药物治疗，还包括生活方式干预，包括改变饮食习惯和使用营养保健品。在这些策略中，n-3 多不饱和脂肪酸（n-3 PUFAs）正在成为一种有前途的药物，能够对抗 PAH 的炎症成分。在这篇叙述性综述中，我们旨在分析 n-3 PUFAs 对 PAH 发病机制和病程影响的临床前证据。尽管缺乏 n-3 PUFAs 对 PAH 在人体中的发生和发展所起作用的证据有限，但临床前研究表明，这些饮食成分可能会影响 PAH 病理生物学的多个方面。进一步的临床研究应测试 n-3 PUFAs 在已批准的临床治疗基础上的疗效。这些研究将提供证据，证明 n-3 PUFA 是否能真正作为一种有价值的工具，提高药物疗法在治疗 PAH 方面的疗效。
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引用次数: 0
Batch-dependent safety of COVID-19 vaccines in the Czech Republic and comparison with data from Denmark 捷克共和国 COVID-19 疫苗的批次安全性以及与丹麦数据的比较。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-27 DOI: 10.1111/eci.14271
Tomáš Fürst, Petr Šourek, Zuzana Krátká, Jaroslav Janošek
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引用次数: 0
A novel framework to assess haematology and oncology registration trials: The THEOREMM project 评估血液学和肿瘤学注册试验的新框架：THEOREMM 项目。
IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
European Journal of Clinical Investigation
Pub Date : 2024-06-27 DOI: 10.1111/eci.14267
Timothée Olivier, Alyson Haslam, Patricia Burke, Isabelle Boutron, Florian Naudet, John P. A. Ioannidis, Vinay Prasad

Background

Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies—ESMO-MCBS and ASCO Value Framework—do not integrate these important shortcomings.

Methods

We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)—that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework.

Results

Not applicable.

Conclusions

Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

背景：方法学上的局限性影响了大量肿瘤学和血液学试验，使人们担心试验结果的适用性。例如，次优对照组或病情恶化后获得最佳治疗的机会有限，可能会使试验结果偏向于试验组获益。除了这些限制不会阻碍药物进入市场这一事实外，其他评估工具，如专业协会开发的评估工具--ESMO-MCBS 和 ASCO 价值框架--并没有整合这些重要的缺陷：我们建议建立一个新的框架，评估血液学和肿瘤学癌症临床试验（随机或单臂）的注册情况，即导致上市授权的试验。该方法的主要步骤是：(1) 组建科学委员会；(2) 通过预先指定、预先登记和协议化的方法确定范围、目标和方法；(3) 对协议进行预先登记；(4) 对影响肿瘤学试验的局限性和偏差进行范围审查，并评估现有的评分或方法；(5) 制定框架中应包括和评估的特征清单；(6) 通过向参与临床试验的高引用率血液学专家和肿瘤学专家发送调查问卷，对每个特征进行评估；(7) 最终确定框架的第一版。结果：不适用：不适用：我们的建议是针对当前试验评估中缺乏对关键限制因素的考虑而提出的。我们的目标是建立一个框架，专门用于评估肿瘤学和血液学领域导致上市授权的单一试验。
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引用次数: 0
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