Table 2.
Summary of included studies
| Study | Study design | Findings |
|---|---|---|
| Albrengues et al [27] | In vivo (mouse) | Transition of murine breast cancer cells to G1/S phase of cell cycle is neutrophil dependent, and NETs inhibition or DNase I prevented or decreased LPS-induced “awakening” in dormant murine and human breast cancer cells. |
| Canna et al [33] | Observational (human) | Elevated CRP and low percentage tumor volume of CD4 + T-lymphocytes both predict poor cancer-specific survival in patients undergoing potentially curative resection for CRC. |
| Carruthers et al [38] | Observational (human) | R status and NLR are associated with overall and disease-free survival and time to local recurrence in patients having preoperative chemoradiotherapy for T3 or T4 rectal cancer. Neutrophil count, lymphocyte count, PLR, CEA, and albumin did not show associations with any outcomes. |
| Chan et al [45] | Observational (human) | Low preoperative and postoperative NLR predicts better median survival than high preoperative ratio, or change from preoperative low levels to postoperative high ratio in patients undergoing curative resection for CRC. |
| Cools-Lartigue et al [23] | In vivo (mouse) | Intravascular NETs are generated and are associated with trapping of circulating tumor cells. NET trapping is associated with increased metastatic disease. This is decreased by NET inhibitors (DNAse or neutrophil elastase inhibitor). |
| Crozier et al [34] | Observational (human) | Preoperative CRP, but not CRP on POD2, predicts poor cancer-specific survival in patients undergoing potentially curative resection for CRC. |
| Crozier et al [35] | Observational (human) | Emergency presentation and elevated mGPS were predictive of poor cancer-specific survival in patients undergoing potentially curative resection for CRC. |
| Inoue et al [25] | Observational (human), in vivo (mouse), in vitro | Albumin can modulate intravascular NETosis, and mice either deficient in albumin or treated with iodocetamine (inhibitor of albumin free thiols) had increased NETosis, which promoted lung predominant metastases after injection of head and neck cancer cells. |
| Kersten et al [43] | Observational (human) | High preoperative CRP correlates with poorer cancer-specific survival in all stages of CRC in patients undergoing any surgery for CRC. Excludes emergency presentation and any patients with infection. |
| Kressner et al [47] | Observational (human) | There is association between perineal infection and local recurrence but not abdominal sepsis and recurrence in patients undergoing potentially curative resection for rectal cancer. |
| Laurent et al [8] | Observational (human) | Postoperative morbidity is associated with increased recurrence in patients undergoing potentially curative liver resection for CRC liver metastases. |
| Mallappa et al [41] | Observational (human) | Preoperative NLR > 5 is associated with CRC recurrence in patients undergoing potentially curative resection for CRC. |
| McDonald et al [54] | In vivo (mouse) | NETs are released during endotoxemia and sepsis. NETs ensnare bacteria. Bacterial trapping is increased by 4-fold in the presence of NETs. |
| McMillan et al [10] | Observational (human) | Increased cancer stage and preoperative and postoperative CRP were associated with overall and cancer-specific survival in patients undergoing potentially curative resection for CRC. |
| Mori et al [44] | Observational (human) | Higher preoperative CRP was associated with poorer cancer-specific survival in patients undergoing potentially curative resection for CRC, but NLR and PLR were not predictive on multivariate analysis. Low levels of infiltrating CD8 + T-cells in CRC tissue were a predictor of poorer cancer-specific survival. |
| Najmeh et al [57] | In vivo (mouse) | In a murine model of intra-abdominal sepsis, beta-1 integrin expression on cancer cells and NETs facilitates adhesion. This is partially diminished when treated with DNAse 1. |
| Neal et al [42] | Observational (human) | High preoperative NLR and derived NLR, but not PLR or LMR, are predictors of shortened overall and cancer-specific survival in patients undergoing potentially curative liver resection for CRC metastases. |
| Park et al [26] | Observational (human), in vivo (mouse), in vitro | Breast cancer cells can promote NETosis in the absence of infection in mice. GCSF primes neutrophils for NETosis. NETs deposition in human primary and metastatic breast cancer tissue is associated with aggressive tumor subtypes. Treatment with DNase I–coated nanoparticles decreases metastatic tumor burden in mice. |
| Pilsczek et al [19] | Observational (human) | CEA but not PLR or NLR is an independent predictor of 5-y overall and disease-free survival in patients undergoing laparoscopic resection of stage I–III rectal cancer. |
| Portale et al [39] | In vitro | A new mechanism of NET formation was observed. Neutrophils produce NETs in response to S aureus through a process of rapid (5–60 min) vesicular secretion. Mitochondrial DNA contributed minimally to NETs. |
| Proctor et al [36] | Observational (human) | Elevated preoperative mGPS, NLR, PLR, prognostic index, and prognostic nutrition index were predictive of reduced cancer-specific survival in cancer patients with a range of malignancies. mGPS and prognostic index were predictive of reduced cancer-specific survival in CRC. |
| Richards et al [37] | Observational (human) | Tumor necrosis, high preoperative mGPS, low inflammatory infiltrate in CRC tissue, and cancer stage were associated with reduced cancer-specific survival in patients undergoing potentially curative resection of CRC. Tumor necrosis was associated with an increase in mGPS and reduced inflammatory infiltrate. |
| Richardson et al [55] | Observational (human) with ex vivo analysis | Neutrophils isolated from CRC patients having surgery and subsequently stimulated by fMLP, LPS and IL-8 have reduced NETs formation, inhibition of apoptosis, and an increase in phagocytosis in response to surgery. |
| Richardson et al [56] | Observational (human) with ex vivo analysis | NETs levels from neutrophils isolated and stimulated from aforementioned CRC patient cohort and from a cohort of healthy controls are higher from CRC patients, and NETs levels from neutrophils isolated preoperatively may be associated with adverse patient outcomes. |
| Roxburgh et al [12] | Observational (human) | High preoperative mGPS and low peritumoral inflammatory infiltrate are associated with poor cancer-specific survival in patients undergoing potentially curative resection for CRC. |
| Song et al [46] | Observational (human) | NLR is superior to LMR, PLR, and prognostic nutritional index as independent predictor of overall survival and cancer-specific survival in 1,744 patients having curative resection of CRC. |
| Thalin et al [58] | Observational (human) | In a cohort of patients with advanced incurable cancer, NETs were significantly increased in cancer patients compared to groups of severely ill patients and healthy controls |
| Tohme et al [24] | Mixed in vivo (mouse) and observational (human) | Increased postoperative NETosis was associated with > 4-fold reduction in disease-free survival in patients undergoing potentially curative liver resection for CRC liver metastases. In a murine model of liver I/R injury, increased NETosis correlated with increased metastatic disease. This was reduced on treatment with NET inhibitors. |
| Turner et al [40] | Observational (human) | Reversal of a preoperatively high NLR following resection of primary tumor was associated with increased overall survival in patients with metastatic CRC. |
| Yipp et al [53] | In vivo (mouse) |
In a murine model of superficial bacterial skin infection, NETosis (via a non–cell death pathway) was confined to the local environment. The same was shown in humans. |