EClinicalMedicine最新文献

Background: Food restrictions during periods of neutropenia have been widely used in oncology settings to prevent infections. As there is a lack of clearly demonstrated effectiveness, this strategy is being increasingly questioned.

Methods: A multi-national panel of 23 individuals was convened to develop a clinical practice guideline (CPG) on the use of food restrictions to prevent infections in paediatric patients with cancer and haematopoietic cell transplantation (HCT) recipients. It included representation from persons with lived experience and physicians, dieticians, nurses, pharmacists and guideline methodologists working in paediatric oncology/HCT or infectious diseases. Panel members (female n = 15; 65%) were from North America (12, 52%), Europe (8, 35%), South America (2, 9%) and Australia (1, 4%). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to formulate the CPG recommendations based on a systematic review of randomised controlled trials (RCTs). MEDLINE, MEDLINE in-Process and Embase databases were searched from January 1, 1980, to May 7, 2024, with a broad strategy which combined subject headings and text words relating to neutropenia, infection and diet.

Findings: The systematic review, which provided the evidence base for the CPG recommendations, identified 4312 unique citations, of which 52 were retrieved for full-text evaluation. Eight RCTs met the eligibility criteria and informed panel deliberations. Although there was clinical heterogeneity in the food restrictions evaluated, data were consistent in suggesting that food restrictions lack clinically significant benefit in preventing infections. The panel made two conditional recommendations against the use of food restrictions in a) paediatric patients with cancer receiving chemotherapy and b) in the setting of allogeneic and autologous HCT. The panel developed a good practice statement to emphasise the importance of health care organisations and families adhering to local food safety practices.

Interpretation: This CPG provides the first evidence-based recommendations on use of food restrictions to prevent infections in children and adolescents undergoing chemotherapy and paediatric haematopoietic cell transplant recipients.

Funding: This CPG was funded and developed through the POGO Guidelines Program.

Background: While the immediate effects of pulmonary tuberculosis are well-documented, respiratory impacts persisting beyond treatment, particularly in children and adolescents, are less understood. This systematic review aimed to evaluate the current evidence on tuberculosis-associated respiratory impairment and disability in children and adolescents following tuberculosis treatment.

Methods: We searched MEDLINE, Embase, CENTRAL, Global Index Medicus, and preprints from January 1, 2004, to December 5, 2024, to identify studies enrolling children (0-9 years old) or adolescents (10-19 years old) who completed treatment for microbiologically confirmed or clinically diagnosed pulmonary tuberculosis. Eligible studies measured at least one tuberculosis-associated respiratory impairment or disability outcome. Data were analyzed descriptively and stratified into three age groups based on median age of tuberculosis diagnosis: <5 years, 5-10 years, and >10 years. This study was prospectively registered (PROSPERO CRD42024529906).

Findings: We identified 117 studies reporting tuberculosis-associated respiratory impairment or disability outcomes. Of those, five met our inclusion criteria, as over 80% of the identified studies excluded children and adolescents. Following tuberculosis treatment, children and adolescents exhibited significant respiratory impairments. In children <5 years of age, impairment included reduced tidal volume and peak tidal expiratory flow. Among those 5-10 years, approximately 40% exhibited abnormal lung function post-treatment, increasing to 65% in adolescents >10 years. Disability was frequently reported, with 35-50% of children and adolescents experiencing respiratory symptoms and children <10 years showing reduced growth metrics and a diminished quality of life.

Interpretation: Even after successful tuberculosis treatment, children and adolescents can experience respiratory impairments and disability that may reduce their quality of life, ability to participate in activities, and growth potential. The epidemiology and clinical manifestations of these impairments vary by age, reflecting distinct biological and behavioural differences. Future research should prioritize these younger populations to ensure their unique needs and challenges are adequately represented.

Funding: The Robert E. Leet & Clara Guthrie Patterson Trust; Canadian Institutes of Health Research.

Background: We assessed persistence of typhoid immunity conferred by Vi polysaccharide-tetanus toxoid (Vi-TT) conjugate vaccine (TCV) four years post-vaccination and immunogenicity of a booster dose of Vi-TT given at age five.

Methods: In 2018, a phase 3 trial of Vi-TT in Malawi randomised children 1:1 to receive Vi-TT or meningococcal capsular group A conjugate vaccine (control). Subsequently, TCV was licensed and recommended in the region. In 2023, children vaccinated at 9-11 months in the original trial received a second (Booster- TCV) or first (1st-TCV) Vi-TT dose, at age five. Serum collected at days 0, 28, and 160-180 days after vaccination was tested for anti-Vi immunoglobulin (Ig)G and IgA, reported as enzyme-linked immunosorbent assay units (EU)/mL. Seroconversion was ≥4-fold rise in antibody titers from day 0 to day 28 post-vaccination. Safety outcomes included adverse events during follow-up.

Findings: We enrolled 136 children: 72 Booster-TCV and 64 1st-TCV. At baseline, anti-Vi IgG geometric mean titers (GMT) were higher in Booster-TCV (18.8 EU/mL, 95% CI 15.2-23.2) than 1st-TCV (5.7 EU/mL, 4.6-7.2) arms. GMT increased significantly between days 0 and 28 in both arms, with higher levels in Booster-TCV (6867.9 EU/mL, 5794.1-8140.6) than 1st-TCV (2912.0 EU/mL, 2429.2-3490.7) arms, representing a 375.7 and 492.6 geometric mean fold rise, respectively. On day 28, all Booster-TCV children, and all but one 1st-TCV child, seroconverted. Similar trends were seen for IgA. Vi-TT reactogenicity was similar between vaccine arms.

Interpretation: This study demonstrates sustained Vi-TT immunogenicity four years post-vaccination at 9-11 months old, and robust immune response following a booster dose at five years of age, informing policy decisions on TCV use in children.

Funding: Bill & Melinda Gates Foundation (INV-030857).

Background: Globally, some 45 million children under five years of age are wasted (low weight-for-height). Although 2023 World Health Organisation guidelines on their care did not aim to identify optimal weight gain, they did mention 5-10 g/kg/day as a target, which is a change from prior guidelines that recommended 10-15 g/kg/day, when inpatient-only care was the norm. We aimed to inform future policy/programming on weight gain targets.

Methods: For this systematic review and meta-analysis, we searched Embase, Global Health and Medline. The final search was on 23/02/2024. Papers were included if they reported weight gain of children aged 6-59 months with severe malnutrition during inpatient (facility-based), outpatient (home-based), and hybrid treatment (initially inpatient and progressing to outpatient treatment). Summary data were extracted, and quality was assessed using a NICE Quality Appraisal Checklist. Our primary outcome was mean rate of weight gain (g/kg/day) during treatment. We conducted random-effects meta-analysis to describe pooled mean weight gain by programme type. Meta-regression investigated potential associations of weight gain with length of stay and programme outcomes. We registered the study on PROSPERO (CRD42023266472).

Findings: Our search yielded 3173 papers. We reviewed 321 full texts, identifying 126 eligible papers. Of these, 104 papers, including some 240,650 participants, reported weight gain as g/kg/day and were eligible for meta-analysis. Mean rate of weight gain was 8.8 g/kg/day (95% CI: 7.6, 9.9; I² = 97.8%) across 18 inpatient programmes, 3.4 g/kg/day (95% CI: 2.0, 4.7; I² = 99.4%) across 12 hybrid programmes, and 3.9 g/kg/day (95% CI: 3.4, 4.4; I² = 99.7%) across 60 outpatient programmes. We found inconsistent evidence of an association between slower weight gain and higher mortality: there was weak evidence of association after adjusting for programme type (coefficient = -0.4; 95% CI: -0.7, -0.02; p = 0.04; n = 118 programmes). There was high heterogeneity between studies. Details of weight gain calculation methods varied. We found no evidence for publication bias when accounting for programme type (Egger's test p-value = 0.2).

Interpretation: Weight gain in outpatient programmes was markedly slower than in inpatient treatment. Clearer reporting of weight gain and a better understanding of the sequelae of faster/slower recovery is important to set future weight gain targets. Our results set an important baseline for current programmes to benchmark against.

Funding: Medical Research Council/Global Challenges Research Fund, grant number: MR/V000802/1.

Background: MET exon14 skipping mutations (METex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against ALK translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against METex14 positive NSCLC both in vivo and in vitro. The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of METex14 positive NSCLC.

Methods: This is a multicenter single arm phase II investigator-initiated study that enrolled METex14 positive lung cancer after failing first line chemotherapy and/or immunotherapy. Eligible patients received ensartinib 225 mg orally once daily in a continuous 28-day treatment cycle until disease progression, unacceptable side effect, or death. Primary endpoint was investigator-assessed objective response rate (ORR), and the secondary end point included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR) and safety profiles. The study was registered with the Chinese Clinical Trial Registry (ChiCTR2100048767).

Findings: From July 2021 to February 2024, a total of 31 patients were enrolled and received ensartinib. Median follow-up time of the 30 evaluable patients was 9.2 months (95% Confidence Interval [CI], 6.3-not estimable). The ORR was 53.3% (16/30; 95% CI, 35.5-71.2) and DCR was 86.7% (26/30; 95% CI, 74.5-98.8). Median PFS was 6.0 months (95% CI, 3.0-8.8) and median DoR was 7.9 months (95% CI, 4.8-8.7). Adverse events (AEs) were reported in 24 patients (80%), with 7 (23.3%) of grade 3. The most common AEs were rash (14/30, 46.7%), followed by anemia (7/30, 23.3%), increased ALT (7/30, 23.3%), increased AST (7/30, 23.3%), and pruritus (6/30, 20%). No serious adverse events or treatment-related deaths occurred. Importantly, the exploratory ctDNA analysis indicates that clearance of circulating tumor DNA (ctDNA) at four weeks treatment was associated with more favorable treatment outcomes comparing with patients having positive ctDNA.

Interpretation: Ensartinib has a promising anti-tumor activity and manageable safety in previously treated patients with METex14 positive lung cancer.

Funding: This work was supported by the National Natural Science Foundation of China [82370028, 82422001] and the CSCO-MET Aberrant Solid Tumor Research Grant [Y-2022METAZMS-0066].

[This corrects the article DOI: 10.1016/j.eclinm.2023.102419.][This corrects the article DOI: 10.1016/j.eclinm.2025.103117.].

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi).

Methods: We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165).

Findings: With a median follow-up of 7.1 years (interquartile range 5.6-8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%-80%) and OS was 78% (95% CI 61%-89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1).

Interpretation: Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients.

Funding: This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

Background: It is unclear whether weight loss interventions worsen disordered eating in people living with overweight/obesity. We aimed to systematically evaluate the association between weight loss interventions and disordered eating.

Methods: Six databases were searched from inception until September 2024. Trials of weight loss interventions in people with overweight/obesity were included if they reported a validated score for disordered eating on either the Eating Disorder Examination Interview or the Eating Disorder Examination Questionnaire pre- and post-intervention. Interventions included behavioural weight loss programmes (BWL) and pharmacotherapy licenced for weight loss, with or without concurrent psychological support, provided for at least 4 weeks. Pooled standardised mean differences (SMD) in scores of disordered eating were calculated using random effects meta-analyses. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool and the Newcastle-Ottawa scale for randomised and single-arm trials, respectively (PROSPERO ID: CRD42023404792).

Findings: Thirty-eight studies with 66 eligible arms (61 interventions: 29 BWL, 11 BWL + pharmacotherapy, 20 BWL + psychological intervention, 1 pharmacotherapy + psychological intervention) and 3364 participants in total were included. The mean weight change was -4.7 kg (95% CI: -5.7, -3.7). Compared with baseline, disordered eating scores improved by -1.47 SMD units (95% CI: -1.67, -1.27, p < 0.001, I² = 94%) at intervention completion (median of 4 months). Seven randomised trials that directly compared a weight loss intervention to no/minimal intervention reported an improvement of -0.49 SMD units (95% CI, -0.93, -0.04, p = 0.0035, I² = 73%). Sub-group analyses showed: (a) disordered eating scores improved more in people with an eating disorder at baseline compared with people without high scores, (b) no clear evidence that the association depended upon intervention type, and (c) disordered eating scores improved more in trials rated at low overall RoB.

Interpretation: Despite heterogeneity in effect size, weight loss interventions consistently improved disordered eating scores. These findings provide reassurance that weight loss interventions might not worsen disordered eating and may improve it.

Funding: Novo Nordisk UK Research Foundation Doctoral Fellowship in Clinical Diabetes.

Background: Diversity, equity, and inclusion pertaining to race, ethnicity, and related concepts have historically been underrepresented in clinical trials for pharmaceutical drug development, although this is an increasing topic for regulators, payers, and patient advocacy groups. We aimed to develop a summary statistical measure to assess such representativeness.

Methods: A statistical measure using population demographic parameters derived from performance metrics through verbal autopsy research was proposed for using population frameworks in the UK. The summary measure, R-index, was demonstrated using simulation data with population frameworks from the UK (116 Roche UK clinical trials 2013-2022) and then using published clinical trial results (NCT02366143 [March 1, 2015-September 15, 2017], NCT04368728 [July 27, 2020-October 9, 2020], and NCT04470427 [July 27, 2020-November 25, 2020]). R-index was further proposed for use with benchmarking performance in representative trial development for internal processes, external benchmarking, and performance tracking in clinical trial development.

Findings: R-index was derived from a standardized statistical measure called the L1 norm, or Manhattan distance, and then normalized to the maximum theoretical error observed in some populations using population framework or ontology for reporting concepts such as race, ethnicity, and other dimensions of diversity used to characterize patient cohorts. R-index demonstrated desirable qualities in demonstration simulations, including a range of 0-1, ease of calculation and use, and interpretability and flexibility, as data standards in the space of inclusive research continue to develop.

Interpretation: R-index is an interpretable, accessible summary statistic that may be useful for tracking and benchmarking representativeness in inclusive research and related domains. R-index is adaptable to different population frameworks and ontologies across different settings and considerations in terms of underlying population variables.

Funding: F. Hoffmann-La Roche Ltd/Genentech, Inc.