ObjectiveThis study aims to investigate the role of fast-track surgery in preventing the development of postoperative delirium and other complications in elderly patients with colorectal carcinoma.MethodsA total of 240 elderly patients with colorectal carcinoma (aged ≥70 years) undergoing open colorectal surgery was randomly assigned into two groups, in which the patients were managed perioperatively either with traditional or fast-track approaches. The length of hospital stay (LOS) and time to pass flatus were compared. The incidence of postoperative delirium and other complications were evaluated. Serum interleukin-6 (IL-6) levels were determined before and after surgery.ResultsThe LOS was significantly shorter in the fast-track surgery (FTS) group than that in the traditional group. The recovery of bowel movement (as indicated by the time to pass flatus) was faster in the FTS group. The postoperative complications including pulmonary infection, urinary infection and heart failure were significantly less frequent in the FTS group. Notably, the incidence of postoperative delirium was significantly lower in patients with the fast track therapy (4/117, 3.4 %) than with the traditional therapy (15/116, 12.9 %; p = 0.008). The serum IL-6 levels on postoperative days 1, 2, and 3 in patients with the fast-track therapy were significantly lower than those with the traditional therapy (p < 0.001).ConclusionsCompared to traditional perioperative management, fast-track surgery decreases the LOS, facilitates the recovery of bowel movement, and reduces occurrence of postoperative delirium and other complications in elderly patients with colorectal carcinoma. The lower incidence of delirium is at least partly attributable to the reduced systemic inflammatory response mediated by IL-6.

Therapeutic antibodies targeting PD-1 have made major breakthroughs in cancer treatment. However, the majority of colorectal cancer (CRC) cases are microsatellite stable (MSS) and do not respond to anti-PD-1-based immunotherapy. Combination therapy will be an ideal strategy to overcome this limitation. Gegen Qinlian decoction (GQD), a classical traditional Chinese medicine (TCM) formula, has been clinically proven to be effective in the treatment of ulcerative colitis (UC) and type 2 diabetes mellitus. Here, a systemic pharmacological study revealed that GQD acts through multiple targets and pathways in the human body. Combination therapy with GQD and anti-mouse PD-1 potently inhibited the growth of CT26 tumours in a xenograft model. Gut microbiota analysis revealed that combination therapy with GQD and anti-mouse PD-1 significantly enriched for s__Bacteroides_acidifaciens and s__uncultured_organism_g__norank_f__Bacteroidales_S24-7_group . Based on metabolomic analyses, profoundly altered metabolites were identified in the combination therapy group. Two metabolic signalling pathways, namely, glycerophospholipid metabolism and sphingolipid metabolism, were explored. In particular, we found that combination therapy with GQD and anti-mouse PD-1 significantly increased the proportion of CD8+ T cells in peripheral blood and tumour tissues. Direct treatment with GQD and anti-mouse PD-1 increased the expression of IFN-γ, which is a critical factor in antitumour immunotherapy. In addition, combination therapy with GQD and anti-mouse PD-1 downregulated PD-1 and increased IL-2 levels, suggesting that the combination therapy could effectively restore T-cell functions by suppressing inhibitory checkpoints. The application of the Chinese medicinal formula GQD with PD-1 blockade-based immunotherapy can be a novel therapeutic strategy for CRC patients with MSS tumours.

Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.

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