*2.2.3. Presence of distant metastases: M*

Presence of distant metastasis has also been associated with higher NLR [38, 77]. Metastatic tumours were significantly more frequent in patients who had high NLR (exceeding 3.44) assessing 1030 patients with resectable gastric cancer [22]. Significant difference in M0 vs. M1 frequencies by NLR groups was reported by Deng et al. In addition, the mean NLR was 5.00 in M0 cases and 7.82 in M1 cases [47].

In a large study of 491 gastric cancer patients, NLR was significantly associated with peritoneal metastasis. However, it was not an independent predictive factor for peritoneal spread, while tumour morphology, serum level of carbohydrate antigen CA19-9 and lymphocyte count retained independent predictive value [78]. In contrast, evaluating CRP, activated partial thromboplastin time, NLR and hypoalbuminemia, NLR was identified as an independent risk factor of the presence of peritoneal metastasis. The cut-off level was set at 2.37 [79].

#### *2.2.4. TNM stage*

Considering the previously discussed links between NLR and TNM parameters, correlation with TNM stage could be expected as well. Indeed, advanced TNM stage was significantly associated with high NLR [9, 20, 44, 47, 65, 77]. High NLR (exceeding the ROC-set cut-off value of 1.59) was associated with high TNM stage [55]. The mean NLR was 4.73 in stage I–II and 7.07 in stage III–IV [47]. In advanced gastric cancer (stage III–IV) patients, there still was difference between stage III and IV [53].

Statistically significant correlation between cancer stage and high NLR was confirmed also by multicentre [61] and prospective study design [54]. In a prospective study of 1131 surgically treated patients, high NLR (exceeding the median 3.5) was associated with higher TNM stage. The mean NLR was 2.13 in stage I, 2.40 in stage II, 2.53 in stage III and 2.60 in stage IV [54].

Regarding negative reports, no NLR differences by TNM stage were found by Kim et al. who analysed a large group of 601 patients [48].
