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Background <p>Major surgery disrupts circadian homeostasis, amplifying inflammatory and metabolic stress. The clinical implications of restoring temporal alignment on perioperative immune–metabolic recovery and medium-term oncologic outcomes remain incompletely defined.</p> Methods <p>A two-stage prospective study was conducted at the First Affiliated Hospital of Soochow University (2019–2021). Study A (<i>n</i> = 300) characterized perioperative circadian disruption using a multimodal Circadian Rhythm Index (CRI). Study B (<i>n</i> = 240) was a randomized trial comparing standard ERAS with an integrated circadian reinforcement protocol including timed feeding, controlled light exposure, and low-dose melatonin. Co-primary endpoints were serum interleukin-6 (IL-6) AUC₀–₇d and percent change in the Prognostic Inflammatory and Nutritional Index (ΔPINI).</p> Results <p>Surgery markedly reduced CRI (83.5 ± 8.9 → 59.2 ± 11.8, p &lt; 0.001). Lower baseline CRI predicted higher IL-6 peaks and increased complication risk. Circadian reinforcement reduced IL-6 AUC₀–₇d (362 ± 145 vs 518 ± 183&#xa0;pg·day/mL; p &lt; 0.001) and attenuated inflammatory–nutritional deterioration (ΔPINI –16.9 ± 10.3% vs –30.8 ± 11.4%; p &lt; 0.001). Hospital stay was shorter (9 [8–11] vs. 11 [9–13] days; <i>p</i> = 0.002), and the intervention was associated with improved 3-year disease-free survival (HR 0.56 [0.35–0.89]; <i>p</i> = 0.014). Mediation analysis suggested that CRI improvement accounted for 27.8% of IL-6 reduction and 22.4% of ΔPINI benefit. No serious adverse events occurred.</p> Conclusions <p>Perioperative circadian disruption represents a measurable and modifiable component of surgical stress. Behavioral and environmental circadian reinforcement was associated with improved immune–metabolic recovery and favorable clinical trajectories. Integration of circadian-based strategies within ERAS warrants further multicenter validation.</p>

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Restoring circadian homeostasis is associated with immune–metabolic recovery and medium-term oncologic outcomes after rectal cancer surgery: a prospective randomized trial

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Shengjie Pan,
  • Gang Wang

摘要

Background

Major surgery disrupts circadian homeostasis, amplifying inflammatory and metabolic stress. The clinical implications of restoring temporal alignment on perioperative immune–metabolic recovery and medium-term oncologic outcomes remain incompletely defined.

Methods

A two-stage prospective study was conducted at the First Affiliated Hospital of Soochow University (2019–2021). Study A (n = 300) characterized perioperative circadian disruption using a multimodal Circadian Rhythm Index (CRI). Study B (n = 240) was a randomized trial comparing standard ERAS with an integrated circadian reinforcement protocol including timed feeding, controlled light exposure, and low-dose melatonin. Co-primary endpoints were serum interleukin-6 (IL-6) AUC₀–₇d and percent change in the Prognostic Inflammatory and Nutritional Index (ΔPINI).

Results

Surgery markedly reduced CRI (83.5 ± 8.9 → 59.2 ± 11.8, p < 0.001). Lower baseline CRI predicted higher IL-6 peaks and increased complication risk. Circadian reinforcement reduced IL-6 AUC₀–₇d (362 ± 145 vs 518 ± 183 pg·day/mL; p < 0.001) and attenuated inflammatory–nutritional deterioration (ΔPINI –16.9 ± 10.3% vs –30.8 ± 11.4%; p < 0.001). Hospital stay was shorter (9 [8–11] vs. 11 [9–13] days; p = 0.002), and the intervention was associated with improved 3-year disease-free survival (HR 0.56 [0.35–0.89]; p = 0.014). Mediation analysis suggested that CRI improvement accounted for 27.8% of IL-6 reduction and 22.4% of ΔPINI benefit. No serious adverse events occurred.

Conclusions

Perioperative circadian disruption represents a measurable and modifiable component of surgical stress. Behavioral and environmental circadian reinforcement was associated with improved immune–metabolic recovery and favorable clinical trajectories. Integration of circadian-based strategies within ERAS warrants further multicenter validation.