Langenbeck's Archives of Surgery https://doi.org/10.1007/s00423-022-02432-9 ORIGINAL ARTICLE Preoperative neutrophil‑to‑lymphocyte ratio behaves as an independent prognostic factor even in patients with postoperative complications after curative resection for gastric cancer Jaume Tur‑Martínez1,2 · Javier Osorio1 · Noelia Pérez‑Romero1 · Noelia Puértolas‑Rico1 · Manuel Pera3 · Salvadora Delgado1 · Joaquín Rodríguez‑Santiago1 Received: 8 June 2021 / Accepted: 3 January 2022 © The Author(s) 2022 Abstract Purpose The aim of this study was to determine if the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) could be modified by the presence of postoperative complications (POC) and their severity in patients with gastric adenocarcinoma resected with curative intent. Methods A retrospective study based on a prospective database of patients with resectable gastric adenocarcinoma treated with radical intention (R0) between January 1998 and February 2012. The primary endpoint was overall survival according to preoperative peripheral blood NLR and postoperative complications. Clinicopathological variables, preoperative blood tests, POC and its severity (Clavien–Dindo classification), type of POC (infectious or not infectious) and mortality were registered. A univariate and multivariate analysis (step forward Cox regression) was performed. The Kaplan–Meier method was used to assess overall survival. Results The 147 patients with gastric cancer who had undergone radical resection were included from an initial cohort of 209 patients. Univariant analysis: type of surgery, pT, pN, postoperative complications (Clavien–Dindo ≥ 3) and preopera- tive NLR ≥ 2.4 were significantly associated with survival (p < 0.05). Patients with POC showed worse long-term survival (p = 0.000), with no difference (p = 0.867) between infectious or non-infectious POC. NLR ≥ 2.4 was associated with infec- tious POC (p < 0.001). Patients with preoperative NLR ≥ 2.4 (p = 0.02) had a worse prognosis. Multivariate analysis: pN (p < 0.001), postoperative complications (p < 0.001) (HR 3.04; 95% CI: 1.97–4.70) and NLR ≥ 2.4 (p = 0.04) (HR = 1.55; 95% CI: 1.02–2.3) were independent prognostic factors. Conclusion The preoperative inflammatory state of patients with gastric cancer measured by NLR behaves as an independent prognostic factor, even in patients with POC. Keywords Gastric cancer · Neutrophil-to-lymphocyte ratio · Preoperative systemic inflammation · Postoperative complications Introduction * Jaume Tur‑Martínez It is known that preoperative systemic inflammatory jaume.tur.martinez@gmail.com response is related to the development, progression and inva- 1 Service of General Surgery, University Hospital Mútua sion of tumour cells and consequently to overall survival [1] Terrassa, Terrassa, Barcelona, Spain in most tumours. 2 Department of Surgery, Universitat Autònoma de Barcelona, Different biological parameters have been identified as Bellaterra, Spain markers of a systemic inflammatory state. Some of the most 3 Section of Gastrointestinal Surgery. Hospital del Mar, relevant markers are neutrophil-to-lymphocyte ratio (NLR) Universitat Autónoma de Barcelona, Hospital del Mar [2], lymphocyte-to-monocyte ratio (LMR) [3], platelets-to- Medical Research Institute (IMIM), Barcelona, Bellaterra, lymphocytes ratio (PLR) [4], Nutritional Prognosis Index Spain 13 Vol.:(0123456789) Langenbeck's Archives of Surgery ([10 × albumin] + [0,005 × lymphocytes]) [5], Glasgow preoperative data were systematically collected: age, gender, Prognosis Score (a combination of C reactive protein and preoperative ASA grade classification (American Society albumin values) [6], systemic immune-inflammatory index Anaesthesiologist), neutrophils, lymphocytes, neutrophil- (neutrophils × platelets/lymphocytes) [7] and derived neu- to-lymphocyte ratio (the optimal cut-off value for NLR was trophil-to-lymphocyte ratio (neutrophil to white blood cells obtained according to the median value of the cohort in – neutrophils) [8]. The most frequently analysed biomarker order to compare higher vs. lower index), tumour location to evaluate systemic inflammatory response is NLR, as it is (superior, middle, distal third or gastric linitis), type of gas- a simple, easy-to-use and inexpensive tool. trectomy (total, subtotal, or other) and type of lymphadenec- Several studies have shown that a high preoperative neu- tomy (according to the Japanese Gastric Cancer Guidelines trophil-to-lymphocyte ratio (NLR) value in peripheral blood 2017) [14]. All cases were discussed in a multidisciplinary tests represents an independent prognostic factor of overall tumour board. survival in different types of tumours, including gastric can- Resected specimens were analysed following the 7th Edi- cer [3, 9]. tion TNM classification [15]. Lauren classification (intes- It has also been proven that postoperative complications tinal, diffuse or mixed) [16] was also specified. Patients (especially severe and infectious ones) are independent prog- with serosa invasion or positive lymph nodes (≥ ­pT3 and/ nostic factors for long-term survival after curative gastrec- or ≥ ­pN1) received adjuvant chemotherapy with mitomycin tomy [10–12]. plus tegafur, according to our hospital protocol. Likewise, preoperative systemic inflammatory response All postoperative complications (POC) occurring dur- and postoperative complications are both going to affect ing the first 30 days after surgery were registered, and their overall survival, but at different moments of the disease. severity was graded with the Clavien–Dindo (C-D) classifi- The preoperative systemic inflammatory state is influenced cation (grade I–II: minor complications; grade III–IV: major by the tumour immunity and may induce anti- or pro-tumour complications which required any interventional treatment response. The presence of postoperative complications or presented organ failure with intensive care support; and (especially more infectious ones) could activate different grade V: mortality) [17]. Complications were also divided pro-tumour pathways and impair survival [13]. into infectious and non-infectious. Infectious complica- Given the influence on the survival of preoperative sys- tions were classified according to the previous description temic inflammation and systemic inflammation following published by our group [18]: Sepsis was defined as the postoperative complications, both factors should be analysed presence of two or more systemic inflammatory response together to ensure the independent predictive value of each syndrome criteria. Intraabdominal infection was defined as parameter. (i) an abscess or diffused infection within the abdominal The aim of this study was to determine if the prognostic cavity diagnosed by ultrasound or computed tomography, value of the preoperative NLR could be influenced by the with positive culture; (ii) the presence of an anastomotic presence of postoperative complications in patients with gas- leakage (defined as full-thickness gastrointestinal defect tric adenocarcinoma resected with curative intent. involving the anastomosis); (iii) duodenal stump fistula (bile or purulent drainage from a drain placed close to the duodenal stump); (iv) pancreatic fistula (drain output with Methods amylase content) or (v) acute cholecystitis. Respiratory sep- tic complications included pneumonia (defined as new or Data collection progressive infiltrate on chest X-ray, accompanied by fever, leukocytosis or leukopenia and purulent sputum, for which This is a retrospective observational study using a prospec- antibiotic treatment was started) and pleural empyema. tively maintained database including all patients treated in Wound infection was defined as a deep surgical site infec- the University Hospital Mútua Terrassa (Barcelona, Spain) tion that required treatment with antibiotics agents or super- with gastric adenocarcinoma undergoing gastric resection ficial wound drainage. Urinary tract infection was defined with curative intent (R0) from January 1998 to February according to positive urine culture and clinical findings 2012. The study was approved by the ethical committee (fever, urgency, frequency, dysuria or suprapubic tender- of our hospital (Acta 10/2019). Exclusion criteria are age ness). Finally, catheter-related bloodstream infection was under 18 years old, chronic inflammatory or autoimmune defined as bacteraemia/fungemia in a patient with an intra- illness, neoadjuvant chemotherapy and/or radiotherapy, R1 vascular catheter with at least one positive blood culture and R2 resections, intraoperative finding of carcinomatosis obtained from a peripheral vein and no other apparent source and palliative surgery. The preoperative study included gas- for the bloodstream infection except the catheter. tro-oesophageal endoscopy, thorax-abdomen-pelvis CT and Postoperative follow-up was done according to interna- blood tests almost two weeks before surgery. The following tional guidelines [19, 20] with clinical examination 1 month 13 Langenbeck's Archives of Surgery after discharge, a general blood test with tumour markers and clinical examination every six months and annual abdomi- nal CT scan and gastroscopy, until a 5-year follow-up was achieved for initial stages (pTis, pT1N0M0). All other stages were followed with gastroscopy and abdominal CT every six months during the first two years and then annually. Primary endpoint The primary endpoint was overall survival, according to preoperative peripheral blood NLR and postoperative complications. Statistical analysis Data are shown as frequencies and percentages for categori- cal variables or as median (interquartile range) for quantita- tive variables. Chi-square was used to analyse if the patients with higher preoperative NLR had suffered more postopera- tive complications and more severe complications. Overall survival was calculated from the date of surgery until death from any cause or the date of the last follow-up in living patients. A descriptive statistical analysis and a univariate and multivariable Step Forward Cox regression was per- formed for the prognostic factors. Kaplan–Meier curves according to NLR with the presence or not of POC were plotted and compared using log-rank statistics. The SPSS software package (SPSS Inc, Chicago, IL, USA), version Fig. 1  Flow-chart of patients’ selection. NLR, neutrophil-to-lympho- 25, was used to manage patient data and perform statistical cyte ratio; POC, postoperative complications analyses. anastomosis leak (8.8%) and pneumonia (5.4%). Thirty-six Results patients (24.5%) presented one POC, 18 (12.2%) patients had 2 and 6 (4%) patients had ≥ 3 POC. Cohort data Patients with high preoperative NLR (p = 0.69) did not present more POC. The postoperative mortality rate at Of the 209 patients with resectable gastric cancers, 62 30 days was 6.1%. were excluded because they did not meet the inclusion criteria (47 patients) or because they lacked preoperative Preoperative NLR results leukocyte count data (15 patients) (Fig. 1). A total of 147 patients were included for analysis, with a median follow- Median preoperative leukocyte counts and ratios were neu- up of 43.9 months [1–204]. Table 1 shows the clinical and trophils 4.2 × ­109/L (1.6–14.2), lymphocytes 1.8 × ­109/L pathological variables of included patients: median age was (0.4–3.9) and NLR 2.4 (0.8–16.4). The 50th percentile of 67.5 years [33–92], with a majority of men (65%). The most NLR (2.4) was used as a cut-off value. The sample was common ASA classifications were ASA-II (68%) and ASA- divided into two groups according to NLR value. Both III (20%); 46% of tumours were distal third; most of the groups had similar clinical characteristics, histological types patients were treated with a subtotal gastrectomy and D2 and tumour stage, but infectious POC were more prevalent lymphadenectomy (83%). Intestinal adenocarcinoma was the in the NLR ≥ 2.4 group (p < 0.001) (Table 1). most prevalent Lauren histology type (48.3%), and most of Patients with POC showed worse long-term survival the tumours were locally advanced. POC were registered in (p = 0.000) (Fig. 2), with no difference (p = 0.867) between 60 patients (41%), 25 (17%) of them were infectious and 32 infectious (29.1 months [4.10–54.13], 5-year overall sur- (22%) were severe (C-D ≥ 3). All POC are listed in Table 2, vival 21.3 months) or non-infectious POCs (29.9 months being most frequent: intraabdominal abscess (8.8%), [17.18–42.62], 5-year overall survival 25.6 months). 13 Langenbeck's Archives of Surgery Table 1  Descriptive analysis and patients’ distribution according to Table 1  (continued) NLR values NLR, neutrophil-to-lymphocyte ratio; C-D, Clavien–Dindo classifi- Characteristics n % NLR < 2.4 NLR ≥ 2.4 p cation; ASA, American Society of Anaesthesiologist; NC, not corre- sponded 147 n = 71 (%) n = 76 (%) Gender 0.51 Table 2  Description of non-infectious and infectious postoperative Male 96 65 48 (67.6) 48 (63.1) complications Women 51 35 23 (32.4) 28 (36.9) ASA grade 0.35 Non-infectious (%) Infectious (%) 1 15 10.8 6 (8.4) 9 (11.8) Bleeding (3.4) Intraabdominal abscess (8.8) 2 94 68.1 50 (70.4) 44 (57.9) Paralytic ileus (3.4) Anastomosis leak (8.8) 3 28 20.3 11 (15.5) 17 (22.4) Respiratory failure (2.7) Pneumonia (5.4) 4 1 0.7 1 (1.4) 0 (0) NC 9 3 (4.3) 6 (7.9) Upper gastrointestinal bleeding (2.7) Duodenal stump leak (3.4) Tumour location 0.78 Anaemia (2) Abdominal wall abscess (2) Distal 1/3 70 46 33 (46.5) 37 (48.7) Pancreatic fistula (2) Wound infection (2) Medial 1/3 48 32.7 24 (33.8) 24 (31.6) Acute distress respiratory syndrome Urine infection (1.4) Upper 1/3 28 19 14 (19.7) 14 (18.4) (2) Gastric linitis 1 0.7 0 (0) 1 (1.3) Pleural effusion (1.4) Others (4.1) Type of surgery 0.33 Delayed gastric emptying (1.4) Subtotal gastrectomy 100 68 48 (67.6) 52 (68.4) Others (5.4) Total gastrectomy 42 28.6 19 (26.8) 23 (30.3) Others 5 3.4 4 (5.6) 1 (1.3) Lymphadenectomy 0.36 D2 122 83 61 (85.9) 61 (80.3) The group of patients with preoperative NLR ≥ 2.4 D1 25 17 10 (14.1) 15 (19.7) (p = 0.02) also had a worse prognosis (Fig. 3). NLR main- Lauren type 0.39 tained its prognostic relevance (p = 0.00) in patients with Intestinal 71 48.3 32 (45.1) 41 (53.9) NLR < and ≥ 2.4, with and without POC (Fig. 4A, B). Diffuse 44 29.9 26 (36.6) 18 (23.7) Similarly, NLR was also related to survival in the group Mixed 30 20.4 13 (18.3) 17 (22.4) of patients with stage III tumours (34.04 months [95% CI pT 0.48 19.05–49.02] vs. 15.37 months [95% CI 12.44–18.31], pT1 16 10.9 8 (11.3) 8 (10.5) p = 0.01). pT2 42 28.6 24 (33.8) 18 (23.7) In the univariant survival analysis, factors related to pT3 78 53.1 33 (46.5) 45 (59.2) worse long-term survival were the type of surgery, D2 lym- pT4 11 7.4 6 (8.4) 5 (6.6) phadenectomy, serosa invasion (pT3-4), nodal metastasis, pN 0.83 the existence of POC (especially those classified as Cla- pN0 40 27.2 21 (29.6) 19 (25) vien–Dindo ≥ 3) and preoperative NLR ≥ 2.4 (Table 3). pN1 30 20.4 14 (19.7) 16 (21) Multivariant analysis showed that lymph node metastases pN2 29 19.7 15 (21.1) 14 (18.5) pN3a 22 15 11 (15.5) 11 (14.5) (pN) (p < 0.001), presence of postoperative complications pN3b 26 17.7 10 (14.1) 16 (21) (p < 0.001) and NRL ≥ 2.4 (p = 0.04) were independently Postoperative complica- 0.69 associated with poor survival (Table 3). tions No 87 59.2 41 (57.8) 46 (60.5) Yes 60 40.8 30 (42.2) 30 (39.5) Discussion C-D 0.63 0 87 59.2 40 (56.4) 47 (61.8) This study shows that the preoperative systemic inflamma- I–II 28 19.1 13 (18.3) 15 (19.7) tory response of the host correlates with overall survival III–IV 23 15.6 13 (18.3) 10 (13.2) independently in patients with curative gastric cancer resec- V 9 6.1 5 (7) 4 (5.3) tion. Also, postoperative complications and their severity Infectious complications < 0.001 No 35 23.8 25 (35.2) 10 (13.1) were associated with the worst prognosis, but the inflamma- Yes 25 17 6 (8.4) 19 (25) tory response of postoperative complications (which differs Adjuvant Chemotherapy from the inflammation produced by the oncological process) No 64 43.4 31 (43.7) 33 (43.4) did not affect preoperative NLR. Yes 83 56.6 40 (56.3) 43 (56.6) The prognostic value of preoperative NLR has previously been reported for gastric cancer and other types of tumours 13 Langenbeck's Archives of Surgery Fig. 2  Kaplan–Meier curves comparing overall survival in patients with and without post- operative complications Log-Rank test: P=0.00 Number at risk No POC 86 40 32 26 16 14 POC 63 24 24 15 10 6 Fig. 3  Kaplan–Meier curves comparing overall survival according to the neutrophil-to- lymphocyte ratio (NLR) Log-Rank test: P= 0.02 Number at risk NLR < 2.4 71 63 49 41 26 20 NLR ≥ 2.4 76 52 40 30 24 21 13 Langenbeck's Archives of Surgery Fig. 4  Kaplan–Meier curves comparing overall survival according to (A) NLR ≥ 2.4 with and without POC and (B) NLR < 2.4 with and without POC. NLR, neutrophil-to-lymphocyte ratio; POC, postoperative complications [2, 4, 21–27]. It is well known that peripheral blood neu- independently from tumour stage and the presence of POC, trophils, lymphocytes, monocytes and platelets, as well as suggesting that NLR can behave as a reliable marker of the their combination by ratios, behave as inflammatory markers host inflammatory status against the tumour. in patients with cancer and play a relevant role in tumour- However, it has been described [30, 31] that an altered related immunity. However, the relationship between blood preoperative inflammatory state of the patient can favour levels and the local inflammatory tumour microenvironment POC and these POC (especially the infectious and severe has not been established to date. ones) are related to a higher risk of tumour recurrence. It Neutrophils could promote growth and metastasis of could be argued that only morbidity itself has a real influ- tumours through secreting cytokines, chemokines and vascu- ence on long-term prognosis rather than the preoperative lar endothelial growth factor and promote adhesion between systemic inflammatory state [10, 11, 30]. circulating tumoral cells and distant organs, increasing the Our results suggest that the mechanisms through which chance of distant metastases [28]. Moreover, neutrophils preoperative systemic inflammatory response (NLR ≥ 2.4) could also inhibit the antitumour immune function of the influences overall survival were not mediated through the Natural Killer and cytotoxic T cells. Lymphocytes play a development of surgical complications. Both parameters relevant role in tumour-related immunity. Several subtypes were independent prognostic factors. This is an impor- of tumour infiltrating lymphocytes such as CD8 + T cells tant concept because POC are not uncommon after gastric and memory T cells are associated with better outcomes, but cancer surgery and affect almost 40% of patients in this some subsets of T cells, regulatory T cells and Th17 cells study, the most common being anastomotic leaks (8.8%) are related to tumour progression and unfavourable progno- and intraabdominal abscess (8.8%). These results are in sis. However, a high level of absolute lymphocytes count in concordance with recent studies [32]. blood is associated with an antitumour function, inhibition Our results also show the importance of the preop- of tumour progression and favourable prognosis [29]. erative value of NLR in the prognosis and its influence This study showed that pT, pN, type of surgery, type on the overall survival of different anatomopathological of lymphadenectomy, NLR and severity of postopera- stages (TNM classification). NLR significantly influenced tive complications (C-D) were predictors of long-term stages III and IV so that patients with the same TNM stage survival. However, multivariate analysis showed that had different overall survival according to NLR value. only pN, postoperative complications and NLR remained This phenomenon could be explained because most of independent prognostic factors. These findings under- the patients of our cohort had an advanced TNM stage. line that systemic inflammatory status has an important This is an important observation because it allows us to influence on the prognosis of patients with gastric cancer, 13 Langenbeck's Archives of Surgery Table 3  Univariate and Variables Univariant Multivariant multivariate analyses of clinicopathological variables in HR p HR p relation to overall survival Age 1 (0.99–1.02) 0.82 Gender 0.07 Male 1 Women 0.65 (0.40–1.04) Tumour location 0.07 Distal 1/3 1 Medial 1/3 1.23 (0.77–1.96) Upper 1/3 1.43 (0.83–2.47) Gastric linitis 11.52 (1.49–88.75) Type of surgery 0.02 Subtotal gastrectomy 1 Total gastrectomy 1.84 (1.16–2,92) Others 1.83 (0.65–5.10) Lymphadenectomy 0.01 D1 1 D2 0.52 (0.32–0.86) Lauren type 0.18 Intestinal 1 Diffuse 1.44 (0.86–2.40) Mixed 1.57 (0.91–2.71) pT < 0.001 pT1 1.00 pT2 1.20 (0.47–3.05) pT3 2.58 (1.10–6.02) pT4 6.62 (2.24–19.5) pN < 0.001 < 0.001 pN0 1.00 1.00 pN1 1.29 (0.63–2.66) 1.66 (0.85–3.27) pN2 1.46 (0.72–2.95) 1.48 (0.75–2.92) pN3a 2.97 (1.49–5.93) 2.93 (1.48–5.78) pN3b 5.65 (2.89–11.03) 6.42 (3.25–12.70) Postoperative complications < 0.001 < 0.001 No 1.00 1.00 Yes 2.81 (1.85–4.27) 3.04 (1.97–4.70) C-D < 0.001 0 1.00 I–II 2.62 (1.54–4.47) III–IV 3.36 (1.98–5.70) V 49.48 (20.98–117.12) Infectious complications 0.56 No 1 Yes 1.44 (0.41–4.98) NLR 0.01 0.04 < 2.4 1 1 ≥ 2.4 1.77 (1.14–2.75) 1.55 (1.02–2.37) HR, hazard ratio; C-D, Clavien–Dindo classification; NLR, neutrophil-to-lymphocyte ratio 13 Langenbeck's Archives of Surgery differentiate those patients with the same TNM stage and In conclusion, the preoperative systemic inflamma- different long-term survival [33, 34]. tory response in patients with gastric cancer, measured by It is known that surgery and non-infectious complications neutrophil-to-lymphocyte ratio, behaves as an independent (like obstruction, perforation and haemorrhage) are associ- prognostic factor, even in those patients with postoperative ated with the generation of systemic inflammatory response, complications. More prospective trials are necessary to vali- resulting in the suppression of cell-mediated immunity [35]. date these data. The development of postoperative infectious complica- tions results in an up-regulation of innate immune response Acknowledgements We want to especially thank Sylva-Astrik Toros- sian for her assistance in language editing. This study is part of the and the suppression of adaptive immunity, favouring an doctoral programme of the Department of Surgery at Universitat increased risk of recurrence [30]. Autònoma de Barcelona. Previous hypotheses relating to surgical complications and a reduction in survival were based on the paradigm that Authors’ contributions J. Tur-Martínez and N. Puértolas-Rico collected infective complications initiate an inflammatory cascade, data. J. Tur-Martínez and J. Rodríguez-Santiago designed the study, performed statistical analysis and drafted the manuscript. M. Pera, J. activate pro-inflammatory cytokines and vascular growth Osorio, N. Pérez-Romero, N. Puértolas-Rico and S. Delgado revised factors which promote tumour growth and dissemination the manuscript critically and made substantial contribution. All authors [36]. Although the mechanisms are not well known, the approved the final version of the manuscript. systemic inflammatory response induced by the tumour may differ from that induced by surgical trauma or infec- Funding Open Access Funding provided by Universitat Autonoma de Barcelona. tion. An elevated preoperative NLR has been associated with a greater density of CD4 + lymphocytes around the Data Availability Not applicable. tumour, without other specific immune cells, like CD3 + or CD8 + lymphocytes, suggesting a relationship between Code availability Not applicable. peripheral inflammatory response and immune activation in the local tumour microenvironment [37]. In our series, Declarations we found more infectious POC in the NLR ≥ 2.4, in line with previous studies [31, 38], but this phenomenon did not Ethics approval The present study was evaluated and approved by the correlate with differences in overall survival. Ethical Committee of our hospital. Taking all these reasons into account, we should differ- Consent to participate Because of the retrospective character of the entiate preoperative tumour-related inflammation from the study, non-informed consent was required. The study was approved by inflammatory mechanisms of POC, which will influence the ethical committee of our hospital (Acta 10/2019). prognosis in different ways. Consent for publication Not applicable. Another important issue in most studies is the lack of consensus on the cut-off value for NLR. One of the contro- Conflict of interest The authors declare no competing interests. versies of this type of study is the lack of standardisation to determine the cut-off value for NLR, ranging in the literature Open Access This article is licensed under a Creative Commons Attri- from 2 to 5 [33, 39–41]. We used an NLR cut-off value of bution 4.0 International License, which permits use, sharing, adapta- 2.4, based on the median value, with similar results to other tion, distribution and reproduction in any medium or format, as long studies [9, 42]. However, different methods can be used to as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes calculate NLR, such as ROC curve, median value or the use were made. The images or other third party material in this article are of computer X-Tile software [29]. Because of this variability included in the article's Creative Commons licence, unless indicated in the cut-off values, it is difficult to use preoperative NLR as otherwise in a credit line to the material. If material is not included in a clinical standardised prognostic value. Besides, a combina- the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will tion of different preoperative systemic inflammatory markers need to obtain permission directly from the copyright holder. To view a (NLR, LMR, total number of monocytes and lymphocytes) copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. may provide a better predictive value than each one alone, but this has not been confirmed to date [43]. 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