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The analysis of cell-free DNA (cfDNA) has emerged as a cornerstone of minimally invasive liquid biopsies. We summarize the key advancements of the last five years-deepening insights into fundamental cfDNA biology, innovations in wet- and dry-lab approaches, and the amassment of clinical outcome data-and discuss prospects of this field for the coming half-decade.

Fecal microbiota transplant plus dietary change to restore the imbalance of an individual's microbiome to relieve disorders such as inflammatory bowel disease has not been established but has promise. In this commentary, we suggest the need to embrace a more nuanced, personalized approach, one that considers microbial functionality, dietary context, and host compatibility.

The phase 3 STELLAR-303 trial¹ demonstrated a significant overall survival benefit of zanzalintinib plus atezolizumab over regorafenib in refractory microsatellite-stable (MSS) metastatic colorectal cancer, marking the first phase 3 success of an immunotherapy-based regimen in this population. These results may reshape treatment paradigms and renew interest in biomarker-guided immunotherapy for MSS disease.

Background: Dysregulation of bromodomain and extra-terminal domain (BET) proteins causes aberrant acetylation of histones, triggering oncogene expression in malignancies. TQB3617 is an orally administered BET inhibitor that competitively binds to bromodomains and inhibits their activities.

Methods: This phase 1 trial assessed the safety, pharmacokinetics, and efficacy of TQB3617 in patients with relapsed or refractory lymphomas. The primary endpoints were the safety, dose-limiting toxicity (DLT), and the recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and efficacy. The trial is registered with ClinicalTrials.gov: NCT05110807.

Findings: Using a 3+3 dose-escalation design, 39 patients were enrolled and treated with TQB3617 (0.05-0.25 mg) once daily. DLTs were reported in one patient at 0.1 mg with grade 3 herpes zoster and one patient at 0.25 mg with grade 3 thrombocytopenia and subcutaneous hemorrhage. The safety monitoring committee selected 0.1 mg once daily in two 21-day cycles followed by 14 days on and 7 days off in subsequent cycles as the RP2D. The most common grade 3-4 treatment-related adverse event (TRAE) was thrombocytopenia (14/39, 36%). Three patients discontinued study treatment due to TRAEs (all thrombocytopenia). The overall response rate (ORR) was 31% (12/39; complete response in 4 patients), with ORRs of 31% (5/16) in patients with Hodgkin's lymphoma, 31% (5/16) in patients with T cell lymphoma, and 29% (2/7) in patients with B cell lymphoma.

Conclusions: TQB3617 showed an acceptable safety profile and promising efficacy in patients with relapsed or refractory lymphomas.

Funding: This work was sponsored by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and funded by the National Natural Science Foundation of China.

Background: Childhood obesity is a pressing global public health challenge requiring scalable prevention strategies. This study evaluated a tiered school-family-clinic intervention for obesity prevention among primary schoolchildren in China.

Methods: This cluster randomized controlled trial enrolled 1,627 third-grade students (intervention: n = 838; control: n = 789) from six primary schools in Ningbo, China. Intervention intensity was tailored to baseline weight status. In intervention schools, children without overweight or obesity received OptiChild, comprising health education and school weight-management policies. Children with overweight or obesity received SCIENT, adding teacher-led structured physical activity and individualized family dietary guidance from clinical nutritionists, supported by mobile health tools. Control schools maintained standard curricula. The primary outcome was change in body mass index (BMI). Secondary outcomes included BMI Z score, body fat distribution, blood pressure, and health behaviors.

Findings: After one academic year, BMI gain was attenuated in the intervention vs. control group (+0.02 vs. +0.24 kg/m²; mean difference [MD] -0.25; p = 0.006). Overweight/obesity prevalence declined from 24.8% to 18.9% in intervention schools vs. 23.6%-21.0% in controls (p = 0.015). OptiChild slowed BMI increase (+0.08 vs. +0.25 kg/m²; MD -0.19; p = 0.048) in children without baseline overweight and reduced incident overweight/obesity by 68% (1.1% vs. 3.5%; p = 0.007). SCIENT reduced BMI (-0.19 vs. +0.21 kg/m²; MD -0.38; p < 0.001). Both interventions improved health behaviors, with no adverse events reported.

Conclusions: A tiered school-family-clinic intervention effectively mitigated BMI gain and reduced obesity prevalence, with promising implications for broader public health adoption.

Funding: Major Science and Technology Projects for Health of Zhejiang Province.

Background: Meckel's diverticulum is a mostly asymptomatic anatomic anomaly of the small intestine. Frequently, ectopic mucosa can be found within, potentially causing complications such as hemorrhage. In 0.5%-3.2% of symptomatic patients with Meckel's diverticula, a neoplasm is found.

Methods: Here, we report an extremely rare case of ectopic biliary adenocarcinoma arising from the tip of an incompletely detached Meckel's diverticulum and infiltrating the adjacent abdominal wall in a 79-year-old patient. Moreover, we review the literature on the seldom occurrences of adenocarcinoma in Meckel's diverticula and potential treatment strategies.

Findings: Initially believed to be a soft tissue tumor of the abdominal wall, biopsy results showed adenocarcinoma with CA19-9 and CK7 expression. Hence, open surgery with en bloc oncologic small intestine resection was performed. The patient was discharged with normal bowel passage after an unremarkable postoperative period. Adjuvant chemotherapy was recommended; however, to date, no standard treatment for adenocarcinoma arising from a Meckel's diverticulum has been agreed upon.

Conclusion: The successful surgical resection and ongoing disease-free survival highlight the importance of recognizing and managing malignancies in ectopic embryonic remnants. This case contributes valuable insight into the diagnosis, behavior, and treatment considerations of ectopic malignancies.

Funding: This research has not received any external funding.

Background: Coagulation factor XI (FXI) influences both thrombotic risk and myocardial function, making its relationship with mortality crucial for guiding therapies, especially in coronary artery disease (CAD).

Methods: We analyzed data from 3,170 participants who underwent coronary angiography; 67% were diagnosed with CAD. Participants were followed for a median of 14.5 years. Mortality risk was assessed using Cox proportional hazards models with restricted cubic splines and Wald statistics. Models were adjusted for age, sex, BMI, and further cardiovascular risk factors. Interactions between FXI activity, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and CAD were explored.

Findings: A U-shaped association between FXI activity and mortality was observed (p = 0.027), with the lowest risk at an FXI activity of 115.6%. Among patients without CAD, this U-shaped relationship persisted. In contrast, patients with CAD demonstrated a linear relationship, where higher FXI activity correlated with increased mortality (p interaction < 0.0001). NT-proBNP levels significantly modified these associations, particularly in patients with CAD.

Conclusions: These findings emphasize the dual role of FXI activity in hemostasis, which could have profound implications for pharmacological interventions. The variable effects of FXI activity based on underlying cardiovascular conditions suggest that a personalized approach to treatment is necessary. Consequently, future studies on FXI inhibitors should carefully examine these modulating factors to optimize therapeutic strategies.

Funding: The LURIC study was supported by the Ludwigshafen Heart Centre and academic collaborators, including the universities of Freiburg, Ulm, and Düsseldorf and the Centre Nationale de Genotypage in France, through internal institutional resources.

Background: Chronic skin wounds, such as diabetic ulcers, represent a significant healthcare challenge due to their complex microenvironment, which includes bacterial infections, excessive inflammation, and impaired circulation. Traditional wound dressings often fail to address these multifaceted issues, while advanced hydrogel dressings, despite their advantages, are limited by susceptibility to bacterial growth, reliance on labile therapeutic components, and concerns about long-term biocompatibility.

Methods: We developed a sprayable low-temperature plasma (LTP)-infused hydrogel dressing as an effective solution for wound management. LTP, a room-temperature ionized gas enriched with reactive oxygen and nitrogen species, is known for its potent antibacterial properties and wound-healing potential.

Findings: By incorporating LTP-generated oxidizing species (Ox, including H₂O₂, NO₂^-, and NO₃^-) into a sprayable thermosensitive F127 hydrogel (Ox@F127), the Ox@F127 hydrogel dressing demonstrated broad-spectrum antibacterial efficacy and accelerated wound healing. In various skin-wound models, including bacteria-infected wounds in mice and diabetic minipigs, Ox@F127 effectively inhibited E. coli and MRSA infections and promoted wound healing. Mechanistic insights from RNA sequencing revealed that Ox@F127 enhances extracellular matrix remodeling, collagen regeneration, angiogenesis, and epithelialization.

Conclusions: This simple yet innovative approach offers a promising solution for chronic wound management, with significant potential for safe and effective clinical translation.

Funding: Funding was provided by a McGill start-up package, the National Key Research and Development Program of China, Guangdong Basic and Applied Basic Research Foundation, Shenzhen Science and Technology Major Project, Shenzhen Medical Academy of Research and Translation, and Shenzhen Outstanding Talents Training Fund.

Background: Non-invasive assessment of improvement in fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is an important clinical problem. We aimed to develop and validate the fibrotic MASH resolution^VCTE index, a non-invasive tool for identifying fibrotic MASH resolution and predicting liver-related events (LREs).

Methods: We collected data from 2,017 individuals who had two liver biopsies, separated in time, across 40 centers in the first dataset. This dataset included two independent cohorts, which were used to develop and externally validate the tool (including the baseline and change in acFibroMASH index plus change in serum alanine aminotransferase levels). The second independent dataset, comprising 17,949 patients who underwent vibration-controlled transient elastography (VCTE) at 16 centers, was used to examine associations between the developed index and the risk of incident LREs.

Findings: After application of the inclusion and exclusion criteria, 252 and 8,752 patients were included in the first and second datasets, respectively. The fibrotic MASH resolution^VCTE index accurately identified fibrotic MASH resolution with an area under the receiver operating curve (AUROC) of 0.82 (95% CI 0.74-0.90) in the derivation cohort and 0.80 (95% CI 0.72-0.88) in the validation cohort. Patients with a fibrotic MASH resolution^VCTE index >0.61 had a substantially lower risk of incident LREs than those with an index <0.24 (adjusted-hazard ratio 0.043). The index achieved AUROCs of 0.86 and 0.87, respectively, for predicting the 5- and 10-year probability of not developing LREs.

Conclusions: This global multicenter study suggests that the fibrotic MASH resolution^VCTE index may offer a non-invasive approach to estimate fibrotic MASH resolution and stratify long-term risk of LREs.

Funding: National Natural Science Foundation.