The risk of nodal disease in patients with pathological complete responses after neoadjuvant chemoradiation for rectal cancer: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: This systematic review and meta-analysis seek to evaluate the prevalence of nodal disease in rectal cancer patients with pathological complete responses (pCR) after neoadjuvant chemoradiotherapy (ypT0N+). METHODS: This study conformed to the PRISMA guidelines. A search was performed on major databases to identify relevant articles. Meta-analyses of pooled proportions were performed on rectal cancer with pCR and ypT0N+. Meta-regression was undertaken to identify sources of heterogeneity, and the Newcastle-Ottawa Scale (NOS) was employed to assess the risk of bias. RESULTS: A total of 18 studies were included, totaling 7568 patients. The overall risk of bias was low, since all studies scored 6 and above out of 9 on the NOS. Preoperatively, the pooled proportions of patients with T3/T4 tumors and clinically positive nodal disease were 84.08% (95% CI 74.19 to 91.99%) and 52.14% (95% CI 35.02 to 69.00%) respectively. The prevalence of pCR in the whole pool was 18.52% (95% CI 13.31 to 24.35%; I2 = 93.85%; P = 0.00), and meta-regression showed a significantly negative relationship with patient age (ß = - 0.03, 95% CI - 0.03 to - 0.02; P = 0.00). The pooled prevalence of ypT0N+ was 4.61% (95% CI 2.41 to 7.28%; I2 = 52.27%; P = 0.01), and meta-regression demonstrated a significantly positive relationship with male gender (ß = 1.06, 95% CI 1.00 to 1.12; P = 0.04). CONCLUSION: There is a small risk of ypN+ in patients with pCR after neoadjuvant CRT and surgery for rectal cancer. However, further research is warranted to establish these findings and to identify predictive factors for this specific group of patients.

S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy.

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease.