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Background: Cryptoglandular anal fistula is a condition that significantly impairs quality of life in patients. Despite the recent development of the Anal Fistula Core Outcome Set (AFCOS), which identified ten key outcomes, variation in outcome definitions and measurement instruments hampers comparability across studies and limits evidence synthesis. An essential final step to improve future comparability is the development of a Core Outcome Measurement Set (COMS) aligned with AFCOS; this study aimed to establish such a COMS through an international, consensus-driven process.

Methods: This study was conducted in three phases according to the Core Outcome Measures Effectiveness Trials (COMET) methodology. Phase 1 included a scoping review to identify definitions and measurement instruments for all AFCOS outcomes. Phase 2 involved summarising available evaluation of psychometric properties and overall feasibility of each instrument according to the COSMIN criteria. Phase 3 consisted of an international two-round Delphi survey conducted from September 2023 until May 2024 and a final consensus meeting in June 2024 with patients and healthcare professionals to agree on definitions, measurement instruments and timepoints.

Findings: In Delphi round 1, 92 of 110 participants (85 health professionals, 7 patients, from 18 countries) completed the survey (84% overall response). Many instruments had insufficient content validity when evaluated by patients. In round 2, 70 of 76 participants (63 professionals, 7 patients) completed the survey (92% response). A final consensus meeting was attended by 27 participants (26 clinicians and 1 patient representative). Clinical fistula healing was defined as the absence of discharge symptoms, abscess, infection or inflammation, with no recurrence or persistence for ≥6 months. Recurrence was defined as the reappearance of symptoms after this healing period. Radiological healing was defined as complete resolution of any visible fistula tract and inflammatory mass, ± fibrosis on MRI. Development of an additional fistula was defined as a separate, anatomically distinct tract. Complications were classified according to the Clavien-Dindo system, and reinterventions were limited to surgical or radiological procedures. The Anal Fistula Quality of Life Scale was selected to assess quality of life, fistula symptoms and psychological impact, the Vaizey score to assess continence, and a numerical rating scale to assess patient satisfaction. Timepoints were set at 3- and 12-months post-treatment.

Interpretation: AFCOMS provides standardised outcome definitions and measurement tools for use in future cryptoglandular anal fistula research, enhancing reporting consistency and enabling evidence synthesis.

Funding: There was no external funding for this study. The study was conducted independently by the authors.

Background: Mild autonomous cortisol secretion (MACS) is associated with an increased morbidity and mortality. Treatment options range from adrenalectomy to conservative management of comorbidities, but evidence on the effects of medical treatment is scarce. We therefore aimed to investigate the metabolic effects of evening metyrapone treatment in patients with MACS.

Methods: We did a prospective, open-label, proof-of-concept trial (EudraCT: 2022-000161-40). Patients with uni-or bilateral adrenal incidentaloma and MACS defined by cortisol >1·8 μg/dL after 1 mg-dexamethasone-suppression-testing without clinical signs of Cushing's syndrome were included. Participants were investigated at baseline and after 12 weeks of treatment with metyrapone (500 mg at 6 p.m. and 250 mg at 10 p.m.). Intrahepatic lipid content (IHL) and abdominal visceral/subcutaneous fat mass were measured by magnetic resonance spectroscopy and imaging. Resting blood pressure measurements and blood sampling before and during an oral glucose tolerance test were conducted. IHL was the primary outcome parameter. Wilcoxon-signed-rank-tests were used for statistical analysis.

Findings: Between May 2023 and September 2024, 19 patients were enrolled. Fifteen patients were included in the final analysis (12 female, median age 59 years [IQR 53-64]; median BMI 28 kg/m² [25-32]; median cortisol after 1 mg-dexamethasone-suppression-testing 2·9 μg/dL [2·4-4·6]). Metyrapone treatment significantly lowered median IHL at follow up compared with baseline (3·85% of water signal [IQR 1·52-6·58] vs 1·92% [1·12-5·91]; p = 0·010). Median fasting insulin (12·6 μlU/mL [IQR 10·5-19·5] vs 9·3 μlU/mL [7·2-14·4]; p = 0·041), median c-peptide concentrations (3·0 ng/mL [2·5-4·4] vs 2·8 ng/mL [2·2-3·4], p = 0·024) and inflammatory parameters (median leukocyte count 8·1 G/L [6·4-8·9] vs 7·4 G/L [6·0-8·8]; p = 0·018; median neutrophil-to-lymphocyte-ratio 2·39 [1·74-2·75] vs 2·04 [1·47-2·55]; p = 0·00020) improved. Median systolic (128 mmHg [IQR 122-139] vs 122 mmHg [119-126]; p = 0·075) and diastolic (83 mmHg [80-95] vs 78 mmHg [75-91]; p = 0·10) blood pressure was non-significantly lower at follow up. No patient reported adverse symptoms of adrenal insufficiency during the study period.

Interpretation: Treatment of MACS with evening doses of metyrapone lowers hepatic lipid content and improves the metabolic risk profile and might offer a novel therapeutic approach.

Funding: Esteve (formerly HRA pharma) to the Medical University of Vienna (PI:PW).

Background: This study aimed to assess the clinical outcomes of transarterial chemoembolization (TACE) with immune checkpoint inhibitors (ICIs) plus vascular endothelial growth factor (VEGF) inhibitors or tyrosine kinase inhibitors (TKIs) (combination therapy) versus TACE monotherapy as a first-line treatment for intermediate-stage hepatocellular carcinoma (HCC).

Methods: This nationwide, retrospective cohort study employed a target trial emulation framework with a cloning-censoring-weighting approach. Patients with intermediate-stage HCC receiving either combination therapy or TACE monotherapy between January 2018 and December 2022 in China were included. Co-primary outcomes were overall survival (OS) and progression-free survival (PFS) per modified Response Evaluation Criteria in Solid Tumors (mRECIST), assessed using restricted mean survival time (RMST). Hazard ratio (HR) was additionally estimated using Cox proportional hazards models for reference. For both RMST and HR, 95% CIs were obtained by bootstrapping. Secondary outcomes included PFS per RECIST 1.1, objective response rate (ORR) per both mRECIST and RECIST 1.1, and safety. This study is registered at ClinicalTrials.gov (NCT05332496).

Findings: A total of 941 patients were included in the study, with 308 (32.7%) receiving combination therapy, and 633 (67.3%) receiving TACE monotherapy. Median OS was 32.9 with combination therapy versus 23.0 months with TACE monotherapy, with an RMST difference of 9.2 months (95% CI 4.5-14.3, bootstrapped p < 0.001; HR 0.57 [95% CI 0.43-0.70]). Median PFS was 18.0 and 12.9 months in the respective groups, with an RMST difference of 6.7 months (95% CI 3.3-10.7, bootstrapped p = 0.001; HR 0.70 [95% CI 0.58-0.82]). Combination therapy also yielded a higher ORR per mRECIST (60.5% versus 44.3%; p < 0.001). Similar results for PFS and ORR were observed when assessed using RECIST 1.1. Grade ≥3 adverse events occurred in 64 (20.8%) and 43 (6.8%) patients, respectively.

Interpretation: Combining TACE with ICIs and VEGF inhibitors or TKIs was associated with improved OS and PFS than TACE monotherapy, with an acceptable safety profile, supporting its potential as a first-line treatment strategy for intermediate-stage HCC.

Funding: National Natural Science Foundation of China (82130060, 82502493), China Postdoctoral Science Foundation (2025M772071), Jiangsu Provincial Basic Research ProgramNatural Science Foundation-Frontier Leading Technology Basic Research Project (BK20232008), Jiangsu Provincial Medical Innovation Center (CXZX202219), Postdoctoral Fellowship Program of CPSF (GZC20251385), and Natural Science Foundation of Jiangsu Province (BK20251687).

Background: Colorectal cancer survivors have increased risks of subsequent primary cancers (SPCs), but most studies have included individuals with hereditary colorectal cancer syndromes. This study assessed SPC risks for colorectal cancer survivors without a known hereditary predisposition to colorectal cancer.

Methods: We analyzed data from the Colon Cancer Family Registry Cohort, recruiting participants between 1998 and 2012 through population cancer registries in Australia, Canada and the United States, with follow-up every five years (until December 2022). Individuals with pathogenic germline mutations in APC, MUTYH, or DNA mismatch repair genes were excluded. Standardized incidence ratios (SIRs) were calculated by comparing observed cases with expected cases based on age-, sex-, country-, and calendar period-specific incidence rates.

Findings: The study included 7202 (49.8% female) colorectal cancer survivors with a mean age at diagnosis of 55.1 (SD 11.5) years and a mean follow-up of 10.6 (SD 7.45) years. Overall, there was no evidence of increased SPC risk (SIR 1.04, 95% CI: 0.98-1.11). Elevated risks were observed for subsequent primary colorectal (SIR 1.34, 95% CI: 1.14-1.57), hematopoietic (SIR 2.49, 95% CI: 1.92-3.21), liver (SIR 2.25, 95% CI: 1.51-3.36), and thyroid (SIR 1.90, 95% CI: 1.20-3.02) cancer. Early-onset colorectal cancer cases (diagnosed before age 50) had increased SPC risks (SIR 1.43, 95% CI: 1.25-1.64) while those diagnosed at 50 and above did not (p < 0.001).

Interpretation: In non-hereditary colorectal cancer survivors, overall SPC risks are not elevated, but early-onset cases have higher risks and therefore warrant targeted surveillance and follow-up.

Funding: National Institutes of Health (U01 CA167551) and National Health and Medical Research Council (1194392).

Background: Complete surgical resection of retroperitoneal sarcomas (RPS) remains the cornerstone of potentially curative treatment. However, recurrence is common and timing of relapse is thought to reflect tumour biology. We aimed to determine the impact of early recurrence on prognosis in patients undergoing resection of RPS, and to identify preoperative predictors of early recurrence.

Methods: In this international, retrospective cohort study, consecutive patients (aged 19-90 years) with primary, non-metastatic RPS treated between March 2012 and October 2019 at two high-volume referral centres in Milan, Italy and Toronto, Canada were identified from prospectively maintained databases. Patients with Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, desmoid tumour, gynaecologic sarcoma, or GIST were not eligible for inclusion. The primary outcome of interest was overall survival (OS) from diagnosis. Patients were grouped by disease-free interval (DFI) following resection: 0-6, 7-12, 13-18, 19-24, and >24 months. Patients who did not undergo resection served as a reference group. Multivariable analyses evaluated predictors of OS. Existing prognostic tools, such as the Sarculator nomogram and the Inflammatory Biomarkers Prognostic Index (IBPI), were tested as potential preoperative predictors of early recurrence (DFI 0-6 months).

Findings: 651 patients (median age 62.7 years) were included; of whom 566 (87%) underwent resection and 85 (13%) did not. Median follow-up from time of diagnosis was 75.9 months (IQR 58.6-99.5). Of the 566 patients who were resected, 259 (46%) developed recurrence, including 49 (19%) within 6 months. Patients with DFI 0-6 months had similar OS to that of unresected patients (2-year OS: 51.6% vs 42.7%, p = 0.32), while later recurrence was associated with improved OS (p < 0.001). On multivariable analysis, DFI was independently associated with OS, but patients with early recurrence had a hazard ratio for death of 0.96 compared with unresected patients. No preoperative clinical variable, nor Sarculator or IBPI, reliably predicted early recurrence.

Interpretation: These descriptive findings show that nearly one in five patients who recur after resection of primary RPS do so within 6 months, with OS comparable to those not undergoing surgery. Whilst acknowledging the limitations of this retrospective design and that resection is a time-dependent and clinically selected decision, these findings raise questions about the clinical benefit of resection in this subgroup of patients. Improved tools are needed to guide preoperative patient selection and optimise treatment strategies. Further research is warranted.

Funding: This work was partially funded by Italian Ministry of Health - "Ricerca Corrente" funds.

Background: Preeclampsia is a hypertensive pregnancy disorder marked by systemic inflammation and endothelial dysfunction. Sulfasalazine, an anti-inflammatory agent, may have therapeutic potential in preeclampsia. This study investigated its pharmacokinetics, placental transfer, and safety profile of sulfasalazine and its metabolite, sulfapyridine in women with preterm preeclampsia.

Methods: A prospective, open-label pharmacokinetic trial was conducted at two hospitals in Melbourne, Australia, (February 2018-December 2020). Participants between 24+0- and 36+0- weeks' gestation with a singleton, non-anomalous pregnancies and a diagnosis of preeclampsia were included received 3 g/day of oral sulfasalazine. Serial maternal blood samples were collected post-dose. Maternal and umbilical cord blood and placental tissue were collected at birth. Primary outcomes were maternal-fetal safety and pharmacokinetics. Maternal plasma levels of soluble fml-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. All participants receiving at least one dose were included in analyses. The trial was prospectively registered with ANZCTR (12617000226303).

Findings: Twelve participants were enrolled, seven had pharmacokinetic sampling. No serious adverse events occurred relating to sulfasalazine use. Sulfasalazine and its metabolite sulfapyridine were detected in maternal plasma, placenta and in the fetal circulation. Maternal-to-fetal transfer of both compounds was confirmed, with some participants showing higher concentrations in cord blood than maternal blood, suggesting potential active or saturable transport mechanisms. Antiangiogenic biomarkers, including sFlt-1, increased post-treatment in most participants.

Interpretation: Sulfasalazine was well tolerated in women with preterm preeclampsia and showed maternal and fetal exposure. Placental transfer was evident. These findings support the feasibility of sulfasalazine use in this population and warrant further investigation in a larger clinical trial to evaluate efficacy.

Funding: Norman Beischer Medical Research Foundation, University of Melbourne, and NHMRC. Funders had no role in study conduct or manuscript preparation.

Background: Gender affirming hormone therapy (GAHT) is associated with improved mental health outcomes among transgender and gender diverse ('trans') individuals, yet limited evidence examines how mental healthcare utilisation changes following GAHT initiation.

Methods: Using Australian administrative data (2012-2024), we identified trans people initiating oestradiol-based GAHT (e-GAHT) or testosterone-based GAHT (t-GAHT). We applied a dynamic difference-in-differences model to estimate within-individual changes in mental health services and prescriptions (antidepressants, anxiolytics), using future GAHT recipients as controls. Effects were estimated separately by regimen and relative to individuals' utilisation three years before GAHT initiation, up to five years post-initiation, and stratified by age (15-24, ≥25 years) and baseline mental healthcare engagement (above/below mean mental health prescription use).

Findings: 20,358 individuals initiated e-GAHT and 11,883 initiated t-GAHT (mean follow-up 4.1 and 4.9 years, respectively). Prior to initiation, e-GAHT recipients had lower engagement with mental healthcare than t-GAHT recipients. For both regimens, mental healthcare use rose at initiation but declined sharply thereafter, with larger initial increases for e-GAHT recipients. Five years post-initiation, e-GAHT and t-GAHT recipients used 0.29 (95% CI -0.03; 0.60) and 2.59 (95% CI 1.87; 3.31) fewer mental health services, respectively. Mental health prescription use among e-GAHT recipients initially rose and then fell to 0.53 (95% CI 0.20; 0.86) at five years, while t-GAHT recipients used 1.02 (95% CI 0.31; 1.72) fewer prescriptions after five years. Reductions in mental healthcare were more pronounced for individuals with higher baseline mental healthcare engagement as well as older e-GAHT recipients.

Interpretation: Consistent with assessment and support requirements, mental healthcare use increases around the time of GAHT initiation-particularly among individuals with limited prior mental healthcare engagement and younger e-GAHT recipients-then declines substantially over time. Altogether GAHT may help address unmet mental health needs and contribute to longer-term reductions in mental healthcare use and associated costs among trans people.

Funding: This work is supported by the University of Melbourne McKenzie Fellowship (2025MCK182), a Viertel Charitable Foundation Clinical Investigator Award, and a National Health and Medical Research Council Investigator Grant (2034450).

Despite a decrease in child mortality since the establishment of the Millennium Development Goals, children and young people (CYP) continue to face threats to their health and well-being, including acute and chronic diseases, mental illness, and trauma-related injury. Qualitative research is underutilized in certain contexts, yet it is an essential methodology to advance child health outcomes. This paper presents recommendations generated by multidisciplinary experts at the Symposium on Applied Qualitative Research, outlining a value proposition for qualitative inquiry to illuminate the complex social, economic, and environmental factors affecting CYP. We advocate for greater integration of qualitative approaches in paediatrics to center the perspectives, experiences, needs, and preferences of CYP across the research continuum. We also discuss challenges in applied qualitative research in paediatrics and propose expert recommendations to guide best practices to ensure the quality and credibility of qualitative approaches, with the goal of advancing inclusive, responsive, and effective child health interventions, programs, and policies worldwide.

Background: Comorbidity, older age, frailty and socioeconomic deprivation are associated with higher risk of complications and death following resection for colon cancer. Minimally invasive surgical (MIS) resection is associated with earlier recovery, fewer postoperative complications and potentially lower early mortality than open surgical (OS) resection. We investigated the likelihood of receiving MIS vs OS resection by patient characteristics, and whether MIS resection reduces mortality after elective resection for colon cancer.

Methods: We analysed cancer registration data linked to secondary care records of 21,931 patients diagnosed with stage I-III colon cancer in NHS Trusts in England, in 2021 and 2022. We focused on elective operations completed as either MIS resections or OS resections. We used an emulated trial to estimate the impact of MIS resection on one-year mortality (expressed as Average Treatment Effect) compared with OS resection. Inverse-probability-weights with regression adjustment ensured comparability between the surgical groups.

Findings: MIS resection was attempted in 18,264 (83.3% of 21,931) patients and completed in 16,271 (74.2% of 21,931), among whom higher levels of deprivation, frailty, comorbidity and stage at diagnosis were independently associated with lower odds of receiving MIS resection. Observed one-year mortality was 7.7% after OS resection (436 deaths among 5660) vs 2.9% after MIS resection (472 deaths among 16,271). In the emulated trial, the average treatment effect of MIS resection was a reduction in one-year mortality from 6.8% to 3.0%; with the largest absolute reductions among patients aged 85 years or more, frail patients, and those with major comorbidities.

Interpretation: The emulated trial confirms that MIS resection for colon cancer reduces mortality at one year, compared with OS resection. However, patients in higher-risk groups, who were most likely to benefit from MIS resection, were less likely to receive it. The NHS needs to eliminate ongoing inequalities in optimal surgery for colon cancer.

Funding: Cancer Research UK C7923/A29018; Medical Research Council MR/T032448/1 and MR/W021021.