Objective: Neutrophil extracellular traps (NETs) are associated with impaired wound healing in diabetes. This study evaluates the association between NET-specific markers and wound healing among diabetic foot ulcer (DFU) patients treated in a multidisciplinary setting. Approach: Clinical data of diabetic patients with active foot ulcers who presented to our team between January 1, 2016 and June 30, 2017 were recorded. The diabetic ulcer severity score (DUSS) and wound, ischemia, and foot infection (WIfI) score were calculated. NET-specific markers in plasma and wound tissues were tested. The capacity for plasma and platelets to prime neutrophils to release NETs was assessed. The prognostic value of NET-specific markers for wound healing was evaluated. Results: NET-specific markers were significantly higher in DFU patients than in diabetic patients without DFU or healthy controls and were found to correlate positively with DUSS or WIfI score. Elastase levels in ulcer tissue significantly increased in wounds with infections and delayed healing. Higher levels of NET release were observed after the stimulation of plasma or platelets from ulcer-related vessels than from nonulcer-related vessels of the DFU patients. Citrullinated histone 3 (citH3) was identified as a risk factor for wound healing impairment and amputation. The patients with the highest quartile of citH3 levels presented significantly lower healing rates and higher amputation rates than those with the lower three quartiles. Innovation: This study extended current knowledge of NETs on wound healing in DFU patients. Conclusion: NET-specific markers negatively correlated with wound healing in DFU patients, and citH3 is a potential marker.

Objective: The aim of our study was to conduct a systematic review and meta-analysis comparing the survival outcomes of IBD-associated and non-IBD-associated CRC. Summary of Background Data: Investigations comparing the prognosis in CRC patients with and without IBD have yielded conflicting results. Methods: PubMed/MEDLINE, Embase, Web of Science, Cochrane Library were searched for studies evaluating the prognostic outcomes between CRC patients with IBD and those without IBD. Estimates of survival-related outcomes and clinicopathological features in IBD-CRC and non-IBD CRC were pooled through random-effects or fix-effects models. The study is registered with PROSPERO, CRD42021261513. Results: Of 12,768 records identified, twenty-five studies with 8034 IBD-CRC and 810,526 non-IBD CRC patients were included in the analysis. IBD-CRC patients have a significant worse overall survival (OS) with the hazard ratio (HR) of 1.33 [95% confidence interval (CI): 1.20–1.47] than those without IBD. Pooled estimates of cancer-specific survival demonstrated that IBD-CRC patients had a poorer cancer-specific survival than those without IBD with fixed-effect model (HR, 2.17; 95% CI: 1.68–2.78; P < 0.0001). Moreover, ulcerative colitis-associated CRC patients have favorable OS than Crohn’s disease-associated CRC (HR 0.79,95% CI: 0.72–0.87). Compared to non-IBD-CRC, patients with IBD-associated CRC are characterized by an increased rate of poor differentiation (OR 2.02, 95% CI: 1.57–2.61), mucinous or signet ring cell carcinoma (OR 2.43, 95% CI: 1.34–4.42), synchronous tumors (OR 3.18, 95% CI: 2.26–4.47), right-sided CRC (OR 1.62, 95%CI: 1.05–2.05), male patients (OR 1.10, 95% CI: 1.05–1.16), and a reduced rate of R0 resections (OR 0.60, 95% CI: 0.44–0.82). Conclusions: IBD-CRC patients have a significant worse OS than patients with non-IBD CRC, which may be attributed to more aggressive histological characteristics and a lower rate of R0 resections at the primary tumor site. Optimized therapeutic standards and tailored follow-up strategies might improve the prognosis of IBD-CRC patients.

The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.

Background: Ulcerative colitis (UC) is a well-known risk factor for developing colitis-associated colorectal cancer (CAC). However, the molecular mechanism of the pathogenesis of CAC remains unclear. This study aimed to explore candidate genes involved in the tumorigenesis of CAC.Methods: GSE75214 and the Cancer Genome Atlas Program (TCGA) dataset were used to analyze the differentially expressed genes (DEGs) in UC and colorectal cancer (CRC), respectively. Survival-hub genes were identified from these DEGs by sequentially constructing a protein–protein interaction network, selecting hub genes, and conducting survival analysis. Regulatory signatures were also predicted on these genes through the online database. Apc^min/+ and UC mice models were used to validate the expression of the above-predicted molecules. Gene set enrichment analysis and CIBERSORT were performed to explore the enriched molecular pathways and associated tissue-infiltrating immune cells of genes.Results: Here, 376 common DEGs were identified from the GSE75214 and TCGA datasets. Through survival-hub gene selection and in vivo experiments, we confirmed that CXCL10 and CXCL11 were significantly upregulated in UC and CRC. We also proved that miR-34a-5p and miR-203a-5p were potential regulators of CXCL10 and CXCL11. Meanwhile, CXCL10 and CXCL11 may activate the JAK–STAT signaling pathway via the interaction with cytokine receptors in UC. Furthermore, CXCL10 and CXCL11 were positively associated with the tissue infiltration of proinflammatory M1 macrophages in UC and CRC.Conclusion: CXCL10 and CXCL11 may act as the candidate genes involved in the tumorigenesis of CAC and potential therapeutic targets to prevent the development of CAC from UC.

Background: Chronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients. Methods: We studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells. Results: CAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02). Conclusion: In CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development.