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Predominantly prevalent in women of reproductive age, high-grade cervical dysplasia and its subsequent management can be challenging and significantly impact fertility goals. In a randomized controlled phase III trial, Chen et al. demonstrate that photodynamic therapy with APL-1702 is better than placebo for regression of CIN2 lesions and has a good safety profile; further investigations are warranted before it can enter standard clinical practice.¹.

Background: Gut microbiota (GM) predict responses to immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer. However, its role in patients with locally advanced lung cancer undergoing chemoradiotherapy (CRT) combined with consolidation ICIs remains unclear.

Methods: A total of 177 fecal samples were collected pre- and post-CRT. Using 16S ribosomal RNA (16S rRNA) sequencing and metagenomic data from an internal cohort and published studies, the kinetics of microbiota were analyzed using the Wilcoxon signed-rank test, while prognostic factors for progression-free survival (PFS) were identified using Cox regression modeling and machine learning algorithms.

Findings: The GM configuration was unaffected by traditional CRT. However, in cases of CRT with consolidation ICIs, patients with long-PFS showed a higher alpha diversity at baseline, followed by a reduction during treatment, contrasting with the stable diversity observed in the short-PFS group. Enrichment of the symbiotic microbe Akkermansia muciniphila (Akk) after CRT was observed, with its increased abundance correlating with extended distant metastasis-free survival in patients undergoing CRT with consolidation ICIs. Notably, the trend in Akk variation was a prognostic indicator of survival outcomes in patients undergoing CRT combined with ICIs. GM was also involved in the development of treatment-related pneumonia and was a promising predictive marker for severe pneumonia.

Conclusions: CRT with consolidation ICIs has more pronounced effects on the GM than CRT alone in patients with locally advanced lung cancer. The dynamic variation in Akk has predictive potential for patient survival in this context.

Funding: This study was supported by the National Science and Technology Major Project.

Background: Randomized clinical trials (RCTs) in low/middle-income countries (LMICs) frequently produce evidence inconsistent with that conducted in high-income countries (HICs). This study aimed to compare RCT effect estimates in LMICs and HICs.

Methods: We identified RCTs from meta-analyses in six leading general medical journals and the Cochrane Database of Systematic Reviews between 2018 and 2023. Only RCTs that recruited participants after 2006 and used a negative control were included. Within each meta-analysis, RCTs sponsored by and enrolling participants in LMICs were designated as the exposed group, while those sponsored by and enrolling participants in HICs were the control group. Effect estimates were transformed into odds ratios (ORs); within each meta-analysis, ORs from LMICs and HICs were combined separately and compared as a ratio of ORs (RORs). RORs were combined across meta-analyses and subgrouped by patient-reported, investigator-assessed, and hard outcomes (e.g., mortality). An ROR larger than 1 indicated a larger OR from LMICs than from HICs.

Findings: 1,005 RCTs (423 from LMICs and 582 from HICs) were identified from 140 meta-analyses. The overall ROR was 1.73 (95% confidence interval: 1.44-2.08). The RORs were 1.94 (1.45-2.61), 1.78 (1.35-2.35), and 1.04 (0.81-1.34) for patient-reported, investigator-assessed, and hard outcomes, respectively. The ROR decreased to 1.04 (0.87-1.24) when restricted to RCTs with a low risk of bias.

Conclusions: Our study suggested that RCTs from LMICs may produce larger effect estimates than those from HICs, with the difference substantially smaller for RCTs with a low risk of bias, indicating that bias may contribute to the discrepancy.

Funding: This work was supported by the Shenzhen Science and Technology Program, Shenzhen Institutes of Advanced Technology, and China Postdoctoral Science Foundation.

The clinical failure of TIGIT inhibitors resulted from an incomplete mechanistic understanding, lack of predictive biomarkers, and functional redundancy with PD-1. Future success requires a focus on PD-1-refractory tumors, improved humanized models, and co-developed diagnostics, emphasizing rigorous science over rapid commercial development.

Background: Ablative/excisional surgery is the recommended therapy for cervical high-grade squamous intraepithelial lesions (HSILs) but is associated with cervical damage and elevated risk of complications upon subsequent pregnancies.

Methods: This multicenter, randomized, controlled trial compared APL-1702 (2-g ointment containing 5% hexaminolevulinate; photoactivated at 125 J/cm²) versus placebo in adult women with cervical HSILs (randomization ratio: 2:1). Upon completion of 6-month treatment, patients in the APL-1702 group entered into a 6-month extension phase with observation only. The primary efficacy endpoint was treatment response, as defined by normal histology or low-grade squamous intraepithelial lesion (LSIL) histology plus human papillomavirus (HPV) clearance, at 6 months in a modified intent-to-treat (mITT) population.

Findings: A total of 402 women were enrolled. The 6-month response rate was 41.1% (104/253) in the APL-1702 group versus 21.7% (28/129) in the placebo group (p < 0.001). The HPV16/18 clearance rates were 31.4% (49/156) and 15.4% (12/78) in the APL-1702 and placebo groups, respectively (p = 0.011). The rates of treatment-emergent adverse events were 56.8% (151/266) and 56.0% (75/134) in the APL-1702 and placebo groups, respectively. At the end of the 6-month extension period, 54.9% (56/102) of the patients who responded at the end of the 6-month treatment period maintained a response.

Conclusions: APL-1702 significantly increased the 6-month response rate in patients with cervical HSILs versus placebo control, with a favorable safety profile.

Funding: This trial was sponsored by Asieris Pharmaceuticals (Shanghai, China).

Cell-free DNA (cfDNA) has emerged as a pivotal biomarker with significant implications across medical fields, including non-invasive prenatal testing and oncology. As cfDNA reflects the physiological and pathological states of the body, a detailed understanding of the biology of cfDNA, including the origins, production, circulation, and clearance, is crucial for advancing its diagnostic applications. This review offers a detailed account of the current understanding of the biology of cfDNA, integrating findings to explore mechanistic insights underlying the production and clearance of cfDNA. We discuss how this interplay is altered in various pathophysiological states-including cancer, pregnancy, systemic lupus erythematosus, infectious diseases, and transplantation-and highlight areas that warrant further characterization. Understanding these processes is essential in studying cfDNA dynamics in health and disease, providing novel insights that could expedite developments that further expand the utility of cfDNA-based diagnostic tests, and pave the way for more personalized applications of cfDNA.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored.

Methods: Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches.

Findings: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181.

Conclusions: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with the potential to refine prognostication in clinical trials for neurodegenerative diseases.

Funding: This study was funded by Target ALS the Israel Science Foundation (3497/21, 424/22) and the CReATe Consortium. All additional funding can be found under the Acknowledgments.

Network medicine applies fundamental principles of complexity science and systems medicine to integrate and analyze complex structured data, including genomics, transcriptomics, proteomics, and metabolomics, to characterize the dynamical states of health and disease within biological networks. In this perspective, we discuss the major successes of the field and how incorporating techniques based on statistical physics and machine learning in network medicine has significantly refined our understanding of disease networks. Despite these achievements, the maturation of network medicine presents challenges that must be addressed. Limitations in defining biological units and interactions, interpreting network models, and accounting for experimental uncertainties hinder the field's progress. The next phase of network medicine must expand the current framework by incorporating more realistic assumptions about biological units and their interactions across multiple relevant scales. This expansion is crucial for advancing our understanding of complex diseases and improving strategies for their diagnosis, treatment, and prevention.

Neuroendocrine neoplasms (NEN) are heterogenous malignancies classified by morphology, site of origin, and Ki-67 proliferation indices. These complicated classification systems often fail to capture NEN outcome diversity. Molecular profiling advances have revealed distinct genomic portfolios that transcend conventional nosology schema. We highlight current classification limitations and suggest the need for individual molecular tumor portraits as a cornerstone of diagnostic/treatment paradigms.

Background: Avian influenza viruses, frequently identified in wild waterfowl and poultry, have occasionally been transmitted to humans, causing severe respiratory diseases. This report covers the fourth case of a human contracting the H10N3 subtype of avian influenza virus.

Methods: A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. Blood, feces, urine, and bronchoalveolar lavage fluid were collected from the patient for medical analysis during the hospitalization.

Findings: A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. She also had a history of exposure to live poultry. This case represents the fourth documented instance of H10N3 infection in humans. She was treated with a combination of baloxavir marboxil and oseltamivir. She exhibited extensive lung lesions. Additionally, she presented complicating factors, including secondary infection, pneumothorax, and numbness in her feet. She recovered and was discharged on March 27, 2025, amid comprehensive supportive care, which included therapy with baloxavir marboxil, oseltamivir, fluconazole, tigecycline, amikacin, extracorporeal membrane oxygenation, and rehabilitation therapy.

Conclusions: The virus was effectively cleared by the combination therapies. The internal genes of the H10N3 virus in this patient were highly homologous to the corresponding genes from the A/Yunnan/2024 virus (GenBank accession numbers, hemagglutinin [HA] [GenBank: PP555669] and PB-2 [GenBank: PP555666]).

Funding: This work was funded by the Fourth People's Hospital of Nanning - Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) Clinical Treatment Center of Guangxi (Nanning).