EClinicalMedicine最新文献

Background: The precise associations between common clinical biomarkers and hepatocellular carcinoma (HCC) risk remain unclear but hold valuable insights for HCC risk stratification and prediction.

Methods: We examined the linear and nonlinear associations between the baseline levels of 32 circulating biomarkers and HCC risk in the England cohort of UK Biobank (UKBB) (n = 397,702). The participants were enrolled between 2006 and 2010 and followed up to 31st October 2022. The primary outcome is incident HCC cases. We then employed random survival forests (RSF) to select the top ten most informative biomarkers, considering their association with HCC, and developed a point-based risk score to predict HCC. The performance of the risk score was evaluated in three validation sets including UKBB Scotland and Wales cohort (n = 52,721), UKBB non-White-British cohort (n = 29,315), and the Taizhou Longitudinal Study in China (n = 17,269).

Findings: Twenty-five biomarkers were significantly associated with HCC risk, either linearly or nonlinearly. Based on the RSF model selected biomarkers, our point-based risk score showed a concordance index of 0.866 in the England cohort and varied between 0.814 and 0.849 in the three validation sets. HCC incidence rates ranged from 0.95 to 30.82 per 100,000 from the lowest to the highest quintiles of the risk score in the England cohort. Individuals in the highest risk quintile had a 32-73 times greater risk of HCC compared to those in the lowest quintile. Moreover, over 70% of HCC cases were detected in individuals within the top risk score quintile across all cohorts.

Interpretation: Our simple risk score enables the identification of high-risk individuals of HCC in the general population. However, including some biomarkers, such as insulin-like growth factor 1, not routinely measured in clinical practice may increase the model's complexity, highlighting the need for more accessible biomarkers that can maintain or improve the predictive accuracy of the risk score.

Funding: This work was supported by the National Natural Science Foundation of China (grant numbers: 82204125) and the Science and Technology Support Program of Taizhou (TS202224).

Background: New options for RSV prevention are available for the 2023/2024 RSV season, nirsevimab, a monocolonal antibody, and RSVpreF maternal vaccine, that target infants entering their first RSV season. Countries vary in implementation of one or both strategies to reduce the RSV burden among infants.

Methods: This study utilized retrospective cohort data from 47 children's hospitals in the United States Pediatric Health Information Systems (PHIS) database between 2015 and 2019. Patients hospitalized with RSV or bronchiolitis aged 0-15 months were included based on birth timing relative to the RSV season. Annualized hospitalization rates per 100,000 were calculated from extrapolated population estimates. Recommended prevention strategies were applied to age cohorts to compare protection afforded by nirsevimab and maternal immunization strategies.

Findings: 72,209 RSV hospitalizations were included in the study. Compared to those born nine months prior to the season (n = 2116; 375/100,000 per year), those born at the start of the season were 9.44 (9.02-9.89) times as likely to be hospitalized for RSV (n = 19,979; 3542/100,000 per year). Both strategies would prevent most of these hospitalizations. Maternal immunization would not prevent hospitalizations of infants aged two or 3 months at season start, who were respectively 2.95 (2.80-3.10) and 2.22 (2.11-2.34) times as likely to be hospitalized. Proportionally more preterm infants were hospitalized in their second RSV season, resulting in less protection (up to 40% to >80% unprotected).

Interpretation: These findings suggest without a more narrowly targeted strategy, current nirsevimab recommendations may not be as cost efficient for infants born further outside of the RSV season, and those born later in the season who are more likely to be hospitalized in subsequent seasons. Conversely, it may be more beneficial to begin maternal immunization further in advance of the season. Immunization strategies should be based on the RSV seasons within specific regions.

Funding: None.

Background: The substantial and increasing global burden of colorectal cancer (CRC) underscores the imperative to enhance implementation and utilization of effective CRC screening offers. Therefore, we examined the lifetime and up-to-date use of CRC screening tests across various countries, and described utilization trends over time.

Methods: We conducted a systematic review on the extent and recent trends of utilization of CRC screening tests among people 45 years or older in different countries around the globe. PubMed/Medline, Web of Science, and Embase electronic databases were screened for eligible studies from inception to June 30, 2024. The study protocol was registered with international prospective register of systematic reviews (PROSPERO) (CRD42023391344).

Findings: A total of 50 studies, based on nationally-representative data, were finally included - 27 from the United States (US) and 23 from other countries. The overall utilization of CRC screening has steadily increased over time in many countries, reaching 74.9% in Denmark in 2018-2020, 64% in Korea in 2020, and 72% in the US in 2021. Nevertheless, the utilization rates remain far below the national or continental targets in most countries. In contrast to European and Asian countries, where screening was predominantly fecal test-based, the approach in the US was primarily driven by colonoscopy, and the uptake of fecal tests and sigmoidoscopy gradually declined in the past two decades.

Interpretation: Despite ongoing progress in CRC screening offers and utilization, there remains large potential for enhanced roll-out and utilization of effective CRC screening programs for enhanced control of CRC incidence and mortality in the years ahead.

Funding: There was no funding source for this study.

Background: This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored.

Methods: Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20 mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100 mg/m², D1-3, Q3W and cisplatin, 75 mg/m², D1, Q3W or carboplatin, AUC = 5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337.

Findings: From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P = 0.071; ctDNA, P = 0.060) and OS (tissue, P = 0.032; ctDNA, P = 0.031).

Interpretation: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety.

Funding: This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

Background: Various effective treatments for depression exist. We aimed to identify the most effective first-line treatments for new episodes of less and more severe depression (defined by depression scale cut-off scores), to update NICE guidance on the management of Depression in Adults in England.

Methods: Systematic review and network meta-analysis of randomised controlled trials (RCTs) published up to June 2020 (PROSPERO registration number CRD42019151328). We analysed interventions by class and individually. The primary efficacy outcome was depressive symptom change (expressed as standardised mean difference [SMD]). The review for this outcome was updated in November 2023.

Findings: We included 676 RCTs, 105,477 participants and 63 treatment classes. For less severe depression, group cognitive/cognitive behavioural therapy (CT/CBT) class was efficacious versus treatment as usual [TAU], the reference treatment for this population [SMD -1.01 (95% Credible Interval [CrI] -1.76; -0.06)]. For more severe depression, efficacious classes versus pill placebo (reference treatment for this population) included combined individual CT/CBT with antidepressants [-1.18 (-2.07; -0.44)], individual behavioural therapies [-0.86 (-1.65; -0.16)], combined light therapy with antidepressants [-0.86 (-1.59; -0.12)], combined acupuncture with antidepressants [-0.78 (-1.12; -0.44)], individual CT/CBT [-0.78 (-1.42; -0.33)], mirtazapine [-0.35 (-0.48; -0.22)], serotonin and norepinephrine reuptake inhibitors [-0.32 (-0.43; -0.22)], tricyclic antidepressants [-0.29 (-0.50; -0.05)], and selective serotonin reuptake inhibitors [-0.24 (-0.32; -0.16)]. Additional treatments showed evidence of efficacy at the intervention level. Evidence for less and more severe depression was of low and low-to-moderate quality, respectively. In the 2023 update, group yoga and self-help without support emerged as efficacious for less severe depression. For more severe depression, combined group exercise with antidepressants emerged as efficacious, whereas combined light therapy with antidepressants failed to remain efficacious.

Interpretation: Group CT/CBT (and possibly group yoga and self-help) appears efficacious in less severe depression, whereas antidepressants do not show evidence of effect. Combined antidepressants with individual CT/CBT, acupuncture and, possibly, group exercise, individual psychological therapies (behavioural therapies, CT/CBT) alone, and antidepressants alone appear efficacious in more severe depression. Quality of evidence, cost-effectiveness, applicability and implementation issues also need to be considered when formulating clinical practice recommendations.

Funding: National Institute for Health and Care Excellence.

Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.

Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.

Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.

Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.

Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Background: There is emerging evidence on the impact of social and environmental determinants of health on paediatric intensive care unit (PICU) admissions and outcomes. We analysed UK paediatric intensive care data to explore disparities in the incidence of admission according to a child's ethnicity and the degree of deprivation and pollution in the child's residential area.

Methods: Data were extracted on children <16 years admitted to UK PICUs between 1st January 2008 and 31st December 2021 from the Paediatric Intensive Care Audit Network (PICANet) database. Ethnicity was categorised as White, Asian, Black, Mixed or Other. Deprivation was quantified using the 'children in low-income families' measure and outdoor air pollution was characterised using mean annual PM2.5 level at local authority level, both divided into population-weighted quintiles. UK population estimates were used to calculate crude incidence of PICU admission. Incidence rate ratios were calculated using Poisson regression models.

Findings: There were 245,099 admissions, of which 60.7% were unplanned. After adjusting for age and sex, Asian and Black children had higher relative incidence of unplanned PICU admission compared to White (IRR 1.29 [95% CI: 1.25-1.33] and 1.50 [95% CI: 1.44-1.56] respectively), but there was no evidence of increased incidence of planned admission. Children living in the most deprived quintile had 1.50 times the incidence of admission in the least deprived quintile (95% CI: 1.46-1.54). There were higher crude admission levels of children living in the most polluted quintile compared to the least (157.8 vs 113.6 admissions per 100,000 child years), but after adjustment for ethnicity, deprivation, age and sex there was no association between pollution and PICU admission (IRR 1.00 [95% CI: 1.00-1.00] per 1 μg/m³ increase).

Interpretation: Ethnicity and deprivation impact the incidence of PICU admission. When restricting to unplanned respiratory admissions and ventilated patients only, increasing pollution level was associated with increased incidence of PICU admission. It is essential to act to reduce these observed disparities, further work is needed to understand mechanisms behind these findings and how they relate to outcomes.

Funding: There was no direct funding for this project. HM was funded by an NIHR Academic Clinical Fellowship (ACF-2022-18-017).

Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions.

Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906.

Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group.

Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group.

Funding: Funded by Sanifit, a CSL Vifor company.

Background: Radiology-based prognostic biomarkers play a crucial role in patient counseling, enhancing surveillance, and designing clinical trials effectively. This study aims to assess the predictive significance of preoperative CT-based tumor contour irregularity in determining clinical outcomes among patients with renal cell carcinoma (RCC).

Methods: We conducted a retrospective multi-institutional review involving 2218 patients pathologically diagnosed with RCC. The training and internal validation sets included patients at Zhongshan Hospital between January 2009 and August 2019. The external test set comprised patients from the First Affiliated Hospital, Zhejiang University School of Medicine (January 2016 to January 2018), the Xiamen Branch of Zhongshan Hospital (November 2017 to June 2023), and the Cancer Imaging Archive. The contour irregularity degree (CID), quantified as the ratio of irregular cross-sections to the total tumor cross-sections, was analyzed for its prognostic relevance across different subgroups of RCC patients. A novel CID-based scoring system was developed, and its predictive efficacy was evaluated and compared with existing prognostic models.

Findings: The CID exhibited significant discriminatory power in predicting overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS) among patients with RCC tumors measuring 3 cm or larger (all p < 0.001). Multivariate analyses confirmed the CID as an independent prognostic indicator. Notably, the CID augmented prognostic stratification among RCC patients within distinct risk subgroups delineated by SSIGN models and ISUP grades. The CID-based nomogram (C-Model) demonstrated robust predictive performance, with C-index values of 0.88 (95%CI: 0.84-0.92) in the training set, 0.92 (95%CI: 0.88-0.98) in the internal validation set, and 0.86 (95%CI: 0.81-0.90) in the external test set, surpassing existing prognostic models.

Interpretation: Routine imaging-based assessment of the CID serves as an independent prognostic factor, offering incremental prognostic value to existing models in RCC patients with tumors measuring 3 cm or larger.

Funding: This study was funded by grants from National Natural Science Foundation of China; Shanghai Municipal Health Commission; China National Key R&D Program and Science and Technology Commission of Shanghai Municipality.