**3.1. PLR and survival: prognostic implications**

The frequency of perineural growth was not different between high and low NLR groups [22]. The frequency of lymphovascular invasion also was not different between high and low NLR groups in a cohort of 143 metastatic gastric cancer cases [25]. In contrast, vascular or lymphatic invasion was significantly more frequent in patients who had high NLR (exceeding 3.44) assessing 1030 cases of resectable gastric cancer. Hypothetically, the higher capacity for invasive growth could be the reason of more frequent occurrence of R1 in patients presenting with high NLR. However, association between NLR and resection line status (R0 vs. R1 vs. R2) was found by Jung et al., who observed no differences in the frequency of lymphatic,

Several haematological parameters, including NLR, are significantly higher in gastric cancer patients than in healthy individuals [18]. A number of studies have confirmed that patients affected by gastric carcinoma have significantly higher NLR than healthy controls [16, 17]. NLR was also higher in gastric cancer patients if compared with persons having adenoma or benign gastrointestinal stromal tumour: 2.17 vs. 1.62. Excluding the confounding factors, NLR was an independent predictor of gastric cancer, associated with the odds ratio of 1.446,

NLR is influenced by smoking [81]. Such differences are reported in gastric cancer patients as well [25] while other researchers have found no difference [47]. Non-oncological diseases, including both inflammations and such frequent non-inflammatory pathologies as diabetes mellitus and atrial fibrillation, among others, can also influence NLR [82]. Thus, SIR should

Several meta-analyses of NLR in gastric cancer have been carried out. Sun et al. have assessed 19 studies of NLR in gastric cancer. They confirmed the association between high NLR and worse overall, progression- or cancer-free survival, and higher stage. The predictive role was lost for stage IV patients who received palliative surgery only [21]. Nineteen studies were subjected to meta-analysis by Xin-Ji et al. [37]. Elevated NLR was associated with shorter overall (odds ratio (OR) 1.65; 95% CI = 1.47–1.83) and shorter cancer-free survival (OR 1.61; 95% CI = 1.28–1.94). Regarding the tumour characteristics, NLR was associated with presence of lymph node metastasis, and high T (T3 + T4) and high stage (III–IV). The odds ratio for lymph node metastasis, 1.70 (95% CI = 1.05–2.75), for T3 or T4 cancer 2.93 (95% CI = 2.27–3.78) and for stage III–IV: 1.87 (95% CI = 1.48–2.35) as reported by Xin-Ji et al. [37]. By meta-analysis performed by Chen et al. [36], high NLR was associated with poor overall survival (hazard ratio (HR) 2.16; 95% CI = 1.86–2.51) and progression-free survival (HR 2.78; 95% CI = 1.95–3.96). In a meta-analysis of 10 studies, higher NLR was associated with worse overall (HR 1.83; 95% CI = 1.62–2.07), progression-free (HR 1.54; 95% CI = 1.22–1.95) and cancer-

vascular and perineural growth regarding NLR level [53].

**2.3. The diagnostic role of NLR and confounding factors**

be assessed within the frames of complex patient evaluation.

**2.4. Meta-analyses of NLR in gastric cancer**

free (HR 1.58; 95% CI = 1.12–2.21) survival [35].

p = 0.005 [77].

164 Gastric Cancer

Similarly to NLR, platelet to lymphocyte ratio (PLR) has been evaluated as a prognostic and diagnostic marker of gastric cancer. Although the prognostic role has been shown both in surgically treatable and advanced gastric cancer cases, the data are controversial.

Some research groups have demonstrated that PLR could help to predict overall and cancerfree survival of surgically treated gastric cancer patients. Thus, in 377 patients who underwent curative resection for gastric cancer, high PLR was an independent predictive factor for worse overall survival [64]. In 162 patients diagnosed with resectable gastric cancer, high PLR correlated with decreased both overall and cancer-free survival [16].

Later, evaluating several blood test parameters (PLR, NLR, absolute count and relative proportion of neutrophils and lymphocytes, counts of platelets, white and red blood cells as well as mean platelet volume) in 451 surgically treated gastric cancer patients, high PLR was the only independent prognostic marker for poor overall survival, associated with hazard ratio of 1.4 (95% CI = 1.0–1.9). Hence, in this study preoperative PLR was more informative than NLR [83].

PLR has been successfully implemented in complex prognostic score (along with NLR, see also the further description) in order to assess the prognosis in stage I–II gastric cancer. The created score was an independent predictor of overall survival and retained prognostic significance both in stage I and stage II [31].

In contrast, several studies either preferred the NLR as more informative SIR marker, or failed to identify the independent prognostic role of PLR although significant association with survival parameters was found by univariate analysis. In 389 gastric cancer patients who have undergone gastrectomy, elevated PLR was significantly associated with worse overall, cancer-specific and cancer-free survival. The cut-off was estimated by ROC analysis and was 132. However, as a prognostic factor for overall survival, cancer-specific survival and cancer-free survival, PLR was not superior to NLR [47]. PLR was not an independent prognostic factor for overall survival in large Chinese cohort of 591 gastric cancer patients although it was significantly associated with survival by univariate analysis. In the same study, NLR along with age and TNM stage was shown to be an independent prognostic factor [84]. Assessing 207 gastric cancer patients treated by resection, univariate analysis disclosed significant association of PLR (along with serum CRP, albumin, Glasgow prognostic score (GPS), NLR, cancer grade and TNM stage) with overall survival and cancer-specific survival. However, by multivariate analysis, PLR was not an independent predictor of survival, contrasting with NLR, GPS, TNM stage and cancer grade. Glasgow prognostic score and TNM stage were the most robust of the assessed prognostic parameters [63]. Evaluating different SIR markers, namely, GPS, NLR and PLR, as prognostic variables in 324 patients with resected stage III gastric adenocarcinoma, only Glasgow prognostic score along with TNM stage was independently associated with cancer-free and overall survival while PLR was associated with GPS [43]. By univariate analysis, both NLR and PLR were associated with overall survival of gastric cancer patients after gastrectomy. However, none of these parameters was identified as an independent factor by multivariate analysis in this study [45]. A study of 1986 consecutive gastric cancer patients was directly targeting the issue if PLR of NLR is better as a prognostic factor of gastric cancer. Although high PLR was significantly associated with poor prognosis it was not an independent risk factor for decreased overall survival in contrast to NLR. Thus, NLR was preferred [39].

Finally, negative results are reported. In a multicentre study of 245 gastric cancer patients, PLR was not associated with survival [61].

In advanced gastric cancer, many studies have revealed significant and independent association between PLR and survival. However, controversial findings still are reported.

High PLR (exceeding 160) along with high NLR (reaching or exceeding 2.57) and high absolute number of lymphocytes (reaching or exceeding 1500/mm3 ) were significantly associated with shorter median overall survival of 168 locally advanced gastric cancer patients. The median survival in high vs. low PLR groups was 27 vs. 45 months [41].

In advanced unresectable gastric cancer, low PLR (less than 235) correlated with less metastasis and improved response to chemotherapy, longer overall survival and progression-free survival. Changes in PLR after first-line chemotherapy also were indicative of prognosis: survival and response to treatment was better in cases that retained low PLR or switched to low PLR group during treatment [38].

In a cohort of 109 metastatic gastric cancer patients treated by chemotherapy, high PLR (exceeding the cut-off 160) was associated with significantly shorter progression-free and overall survival [67].

In 174 advanced gastric cancer cases treated by chemotherapy, low PLR and normalisation of PLR after one cycle of chemotherapy were independent prognostic markers for better overall survival. Normalisation of PLR was also associated with longer progression-free survival: 5.6 months vs. 3.4 months [57].

In a relatively small study group, PLR lacked prognostic role in 53 patients affected by local gastric cancer and treated with surgery and adjuvant chemotherapy while it had significant prognostic meaning in 50 advanced cases treated by chemotherapy. Interestingly, high platelet count was associated with better overall survival in patients having local disease [56].

Again, many studies have identified significant but not independent association between PLR and survival. In 439 patients affected by metastatic or recurrent gastric cancer, PLR (along with NLR, modified Glasgow prognostic score, previous histology with neural and vascular invasion, albumin, CRP and haemoglobin level) was significantly associated with overall survival, but it was not an independent prognostic factor. In this study design, modified Glasgow prognostic score was the only inflammation-related parameter that was independently associated with survival by multivariate analysis [60]. In 384 patients affected by inoperable advanced or metastatic gastric cancer and treated by palliative chemotherapy, PLR (as well as NLR, leucocytosis, elevated number of neutrophils or platelets, decreased lymphocyte count, hypoalbuminemia, high CRP and Glasgow prognostic score) showed association with overall survival by univariate analysis. By multivariate assessment, PLR had no independent meaning. Only elevated count of neutrophils and Glasgow prognostic score were independent survival predictors by multivariate analysis [68].

As the prognostic role of PLR in gastric cancer is controversial, meta-analyses also have brought contrary opinions. Thus, in a meta-analysis of 8 studies comprising 4513 patients with gastric cancer, there was no association between elevated PLR and overall survival: the hazard ratio was 0.99 (95% CI = 0.9–1.1) as described by Xu et al. [85]. In another meta-analysis comprising 14 cohorts and 6280 cases, PLR was associated with poor overall survival (HR 1.3; 95% CI 1.1–1.5) but not with worse cancer-free survival (HR 1.6; 95% = CI 0.9–2.9). High PLR predicted poor survival in Caucasians, patients receiving chemotherapy and patients at advanced stage [86].

In parallel with NLR research, diversity of cut-off levels have been applied in PLR studies (**Table 3**).

In 377 patients who underwent curative resection for gastric cancer, PLR was independently associated with the development of post-operative complications [64].
