EClinicalMedicine最新文献

Background: Individuals with Lynch syndrome (LS) are advised to undergo pancreatic ductal adenocarcinoma (PDAC) surveillance if their lifetime risk is ≥5%, however, evidence is limited. This study quantifies lifetime risk and survival of three cancers relevant to PDAC surveillance, including PDAC, ampullary carcinoma (AC) and distal cholangiocarcinoma (dCC), to evaluate whether surveillance is justified.

Methods: This retrospective nationwide Dutch cohort study included individuals with LS pathogenic variants (PVs) in MLH1, MSH2, MSH6, PMS2 or EpCAM (identified between 1985 and 2024) and compared them to sporadic cases from the general population (diagnosed between 2000 and 2022). Cumulative incidence (CI) of PDAC, AC and dCC was estimated using Fine-and-Gray models for LS and a CI formula for sporadic cases. Relative risks (RRs) were calculated by comparing CIs. Survival of the cancers was compared between both cohorts using 1:10 matched analyses by age at diagnosis, sex, stage, and year of diagnosis.

Findings: In total, 2605 individuals with LS were included (median age 63.9 years; IQR 53.7-74.0), of whom 1515 (58.2%) were female. PVs were identified in MLH1 (723, 27.8%), MSH2 (895, 34.4%), MSH6 (731, 28.1%), PMS2 (233, 8.9%) and EpCAM (23, 0.9%). By age 75, the combined CI of PDAC, AC and dCC was 3.0% (95% CIs, 1.5-5.8) in MLH1, 3.4% (95% CIs, 2.0-5.8) in MSH2/EpCAM, 1.0% (95% CIs, 0.3-2.7) in MSH6 and 0% in PMS2. No familial-clustering of cancers was observed. Matched survival did not differ between PDACs in LS and sporadic cases. In contrast, survival was better for AC in LS (34.3 months; 95% CIs, 3.2-Inf) compared to sporadic cases (15.5 months; 95% CIs, 9.9-19.3).

Interpretation: In LS, the combined lifetime risk of PDAC, AC and dCC ranged from 0 to 3.4% across different genes, remaining below the 5% risk threshold for PDAC surveillance. Additionally, having an affected relative did not appear to increase risk. These findings suggest that current surveillance recommendations for individuals with LS should be re-evaluated.

Funding: Lynch-Polyposis.

Background: Data on cancer incidence and associated risk factors among women with HIV are limited. We investigated cancer burden among women with HIV.

Methods: We included all women ≥18 years from the two large multicentre observational cohort collaborations (D:A:D and RESPOND). The primary outcomes were incidence of all cancers, HPV-related and common individual cancers including breast cancer, lung cancer, and non-Hodgkin lymphoma (NHL) from 2006 to 2021. Baseline was defined as the latest date of entry into local cohort enrolment and 1st January 2006 for D:A:D and 1st January 2012 for RESPOND. Participants were followed from baseline until the date of first cancer, final follow-up or administrative censoring-whichever occurred first. We assessed risk factors using multivariable Poisson regression by applying robust standard errors and determined a population attributable fraction (PAF) for key risk factors for cancers.

Findings: Among 17,512 women included, median age at baseline was 39.5 years (interquartile range, IQR 32.5-46.0). Over 141,404 person-years (PYS) and a median 9.2 (5.5-10.1) years of follow-up, 832 women were diagnosed with any cancer; incidence rate 5.9 (95% CI 5.5-6.4)/1000 PYS, 163 HPV-related cancers (1.1 [1.0-1.3]/1000 PYS), 150 breast cancers (1.1 [0.9-1.2]/1000 PYS), 94 lung cancers (0.7 [0.5-0.8]/1000 PYS) and 72 NHL (0.5 [0.4-0.6]/1000 PYS). Older age (≥45 vs. <45 years), Southern Europe (vs. Western Europe) and smoking were associated with an increased risk of overall cancers. Lower pre-ART nadir CD4, time-updated CD4, and a prior AIDS diagnosis were associated with lung- and HPV-related cancer. In PAF analysis, smoking and HIV-related factors such as lower current CD4, nadir CD4 and HIV viremia significantly contributed to cancer risk.

Interpretation: Our findings suggest that women with HIV older than 45 years, past or current immunosuppressed or current smokers could be candidates for intensified cancer screening and prevention.

Funding: The Highly Active Antiretroviral Therapy Oversight Committee, The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The Isabel Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Background: Machine Learning (ML) can contribute to reducing child mortality and morbidity in low- and middle-income countries (LMICs), yet its development and clinical adoption remain unclear. This systematic review provides an overview of ML for hospitalised children in LMICs.

Methods: In June 2025, searches in five scientific databases and one scholarly search engine identified 26 eligible peer-reviewed studies using ML on hospitalised children under 18. Studies using only conventional statistics and perinatal data were excluded. Study quality and bias were assessed using PROBAST + AI. Descriptive statistics were used for data analysis. PRISMA reporting guideline was followed.

Findings: These studies were conducted in Asia (58%) and Sub-Saharan Africa (38%), mostly retrospective (62%), and predominantly used patient files (62%). The median sample size was 1291. Prognostic models dominated (69%), primarily targeting mortality (50%). Ensemble methods were most common (50%). The median AUROC was 0.81 (IQR 0.78-0.83). Most models were at a clinical Readiness Level 3-4 (81%). Barriers and facilitators related to data (65%, 34% respectively), implementation (50%, 77%), technology (31%, 42%), and human (19%, 35%) were reported.

Interpretation: We provided evidence of ML's promising performance for LMICs. Mortality prediction was the main focus. Arriving at clinical applications that benefit LMICs, requires investment in high-quality data and alignment to local (clinical) needs.

Funding: This project is part of the EDCTP2 programme (grant number RIA2020I-3294 IMPALA) supported by the European Union.

Background: Understanding experiences of diagnostic investigation for any new screening modality is important to inform the development of pathways for future implementation. We explored experience of diagnostic work-up within the NHS in people with a cancer signal detected result from a blood-based multi-cancer early detection (MCED) screening test in the NHS-Galleri trial (NCT05611632).

Methods: A subset of 41 participants with a cancer signal detected result (with/without a cancer diagnosis), were interviewed 6-months after their result. Participants described their experiences of diagnostic investigation within the NHS. Reflexive Thematic Analysis was used.

Findings: The journey through the period of diagnostic investigation was extremely varied since this was dependent on the predicted cancer site(s). Participant narratives demonstrated wide variation in the required tests, number of contacts with healthcare staff and duration of the whole process. Five themes were interpreted from participants' narratives: i) Feeling prepared for procedures; ii) Needing to advocate; iii) Needing to self-navigate: iv) Speed of the diagnostic process and having to wait; v) Reaching 'the end' of diagnostic work-up.

Interpretation: If MCED screening is implemented in future, it will be important to carefully consider implementation of appropriate diagnostic investigation for patients who have a cancer signal detected. We recommend minimising the length of the diagnostic testing period, offering patient navigation and formulating clear plans for what happens at the end of the patient journey. While our findings highlight important considerations to support positive experiences for those having follow-up tests after a cancer signal detected result, they also have broader application for improvement of cancer diagnostic pathways more generally.

Funding: This work was funded and sponsored by GRAIL Bio UK, Ltd. as a sub-study within the NHS-Galleri trial. GRAIL funded the costs of the data collection as well as staff salaries through a contract with King's College London/Queen Mary University of London.

Background: Diagnostic advancements and classification updates appear to have reshaped the natural history of smoldering multiple myeloma (SMM), though this evolution has not been empirically quantified. We conducted a systematic review to evaluate temporal changes in SMM prognosis.

Methods: PubMed, EMBASE and the Cochrane library databases were searched from January 1990 to November 2025, yielding 1415 reports, of which 14 studies met inclusion criteria. To reconstruct individual-level data, published time to progression (TTP) curves were digitized using a Shiny web application. Kaplan-Meier (KM) survival curves and meta-analyses were generated in RStudio. PROSPERO ID 1068697.

Findings: Progression risk at two and ten years for all-risk patients was 22.8% and 60.1%, respectively; these increased to 44.7% and 85.6% in high-risk patients. Landmark analysis from year five revealed attenuated progression rates: 14.2% and 30.8% for all-risk, and 22.5% and 50.6% for high-risk patients at two and five years post-landmark, respectively. Studies enrolling most patients before 2014 showed higher progression rates than in more recent cohorts (Spearman's rho = 0.645, p = 0.034), but this trend did not reach statistical significance in high-risk groups (rho = 0.360, p = 0.272). Meta-analytic data further supported elevated progression in older cohorts.

Interpretation: SMM appears to follow a more indolent trajectory in recent years, likely due to improved diagnostic precision and exclusion of biomarker-defined or subclinical MM. Enhanced predictive models may better guide therapeutic decision-making, targeting treatment to those most likely to benefit and avoiding the burden of unnecessary intervention in low-risk individuals.

Funding: Supported by the Austrian Forum Against Cancer.

Background: Globally, around 2 million pregnancies each year end in stillbirth, with the majority occurring in low and middle-income countries. The association between gestational diabetes mellitus (GDM) and stillbirth has been widely researched but the evidence is increasingly controversial. The aim of this study is to evaluate the risk of stillbirth associated with GDM, and examine whether this risk differs according to country income status and GDM screening method.

Methods: We searched Scopus, Cinahl, Cochrane Central, ISRCTN, Medline, Embase and Epistemonikos on the 9th May 2025 from inception to May 2025 with no restrictions based on language, study location or time. We included cohort studies that estimated the association of interest. We conducted a random effects meta-analysis by study design and sub-group analyses by country income level and GDM screening method. (PROSPERO CRD4201800057).

Findings: 101 included studies (92,915,856 women) presented unadjusted results, 19 reported adjusted results (63,629,536 women). Meta-analysis of adjusted cohort data did not show evidence of an association between a diagnosis of GDM and the risk of stillbirth worldwide (OR 0.81, 95% CI: 0.68-0.97; I² = 87.7%; n = 19 studies). However, when stratified by country income level a diagnosis of GDM was associated with a reduction in the odds of stillbirth in high income countries (OR 0.73, 95% CI: 0.65-0.82; I² = 31.9%; n = 13 studies), but this was not observed in upper and lower middle income countries, (OR 1.17, 95% CI: 0.71-1.93; I² = 59.7%; n = 6 studies). There were no adjusted estimates from low-income countries. There was no evidence of a difference by GDM screening method.

Interpretation: Increased screening, timely diagnosis and effective management strategies for GDM in high-income countries, such as induction of labour and increased antenatal care, may be responsible for the reduced risk of stillbirth in women with GDM. Further research is needed to identify the optimum strategy for screening and management in low and middle-income settings to reduce preventable stillbirths worldwide.

Funding: None.

Background: Suicide rates have risen among young people, making it a leading cause of adolescent death worldwide. Although several pharmacological treatments have been approved in the context of definite underlying conditions, their broader efficacy in reducing suicidality remains unclear.

Methods: A structured review was conducted on pharmacological treatments for suicidality in under 18s. PubMed, Embase, PsycINFO, and Cochrane Library were searched from inception to 31 July 2025. Eligible studies included patients <18 years with suicidality treated with antidepressants, mood stabilisers, or antipsychotics. Exclusion criteria were non-pharmacological interventions, non-suicidal self-injury-only studies, reviews, and grey literature. Both interventional and observational designs were considered. Four authors independently screened, extracted, and appraised data using Joanna Briggs Institute tools. The primary outcome was suicidality reduction, synthesised narratively. This study is registered with PROSPERO, CRD42024548628.

Findings: Twenty-three articles out of 1747 met inclusion criteria, totalling 2235 participants. Risk of bias across studies was low-to-moderate for nearly all studies (22/23). However, the majority employed weaker study designs and targeted underlying diagnoses, with suicidality rarely assessed as a primary outcome. Esketamine (four studies, n = 211) and ketamine (four, n = 6) use in major depressive disorder induced rapid reduction of acute suicidality within 24 h. In the longer term, lithium (three, n = 923) was beneficial in reducing suicidality in youths with bipolar disorder. Sertraline, citalopram, escitalopram, fluoxetine and duloxetine (six, n = 906) yielded inconsistent results. Other agents, including valproate, lamotrigine and antipsychotics such as clozapine and quetiapine exhibited some benefit in reducing suicidality, but findings were limited to small-scale studies.

Interpretation: Evidence remains scarce and heterogeneous. Esketamine and lithium appear promising for acute and chronic suicidality, respectively. Further high-quality studies investigating suicidal thoughts and behaviours as independent treatment targets are needed to guide clinical decision-making.

Funding: None.