Letter to the Editor: “an updated systematic review, meta-analysis, and trial sequential analysis of the efficacy and safety of en bloc transurethral resection vs. conventional transurethral resection for nonmuscle-invasive bladder tumor”

Dear Editor,

We read with great interest the article by Zeng et al^[1], which through a rigorous randomized controlled trial design demonstrated that preoperative parecoxib significantly reduces the incidence of postoperative delirium (POD) in patients with hyperlipidemia. This effect is attributed to dual mechanisms: inhibition of COX-2-mediated inflammatory responses and postoperative pain control, providing important evidence for perioperative neurocognitive protection. Here, we share some thoughts and suggestions to further enrich the discussion.

In this study, ERBT significantly reduced the tumor recurrence rate at 3–6 months and the same-site recurrence rate at 1 year. This phenomenon may be explored in deeper detail from the multi-step regulatory mechanisms of tumor cell dissemination. Notably, gastrointestinal surgery induces a unique “gut-brain axis” inflammatory response: surgical trauma may compromise intestinal barrier function, leading to endotoxin translocation and systemic release of enteric cytokines (e.g., IL-6, TNF-α)^[2]. These cytokines can activate central microglia via vagal pathways or a damaged blood-brain barrier, triggering neuroinflammatory cascades. Patients with hyperlipidemia often exhibit gut microbiota dysbiosis and intestinal mucosal lipid metabolism abnormalities^[3], which may exacerbate intestinal barrier dysfunction and promote enteric cytokine translocation into the brain, thereby increasing the risk of neuroinflammation-mediated POD. Future research incorporating simultaneous detection of intestinal permeability markers (e.g., diamine oxidase, lipopolysaccharide) and central inflammatory biomarkers (e.g., cerebrospinal fluid PGE2) could clarify parecoxib’s role in regulating gut–brain axis inflammation.

The subgroup analysis revealed that parecoxib was more effective in preventing POD among patients with “mild hyperlipidemia” than those with “marked hyperlipidemia”. This suggests that the severity of hyperlipidemia may influence the neuroprotective efficacy of COX-2 inhibitors. Pathophysiologically, excessive cholesterol in marked hyperlipidemia might promote β-amyloid deposition and degrade blood-brain barrier tight junction proteins (e.g., claudin-5), increasing barrier permeability while reducing drug penetration efficiency^[4]. Such structural and functional abnormalities in the neurovascular unit may impair the delivery of parecoxib to the central nervous system, weakening its inhibition of central inflammation. Combining imaging techniques (e.g., MRI to assess blood-brain barrier integrity) with cerebrospinal fluid drug concentration measurements could further validate this hypothesis. Meanwhile, in the future, network meta-analysis can be used to compare the long-term efficacy of different energy platforms (holmium laser, 2-μm laser, bipolar resection), while incorporating health technology assessment metrics such as operation time and learning curve, so as to establish a technology selection model based on tumor characteristics (such as size and location).

This study provides crucial clinical evidence for perioperative neuroprotection in hyperlipidemic patients. We appreciate the authors’ efforts and commend their contributions to the field. We hope that future research may expand sample sizes, extend follow-up periods, and integrate molecular and imaging techniques to deepen our understanding of the dose-effect relationship and long-term outcomes. These steps would strengthen the evidence base for precision interventions and improve long-term prognoses for surgical patients. We sincerely thank you for authors support.

Ethical approval

None.

Consent

None.

Sources of funding

There is no any funding.

Author contributions

Z.L., Y.Y., and C.W. were responsible for the manuscript. X.W. was responsible for writing and reviewing manuscripts.

Conflicts of interest disclosure

The authors have no conflicts to report.

Guarantor

Xiaoxi Wang.

Research registration unique identifying number (UIN)

None.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

None.