Systematic Review and Meta-Analysis Medicine ® OPEN Prognostic value of lymphocyte-to-monocyte ratio previously determined to surgery in patients with non-metastatic renal cell carcinoma A systematic review and a prisma-compliant meta-analysis ∗ Dario Garcia-Rojo, MDa, , Angel Prera, MDa, Jesus Muñoz-Rodriguez, MDa, Joan Carles Oliva, MSb, Arturo Dominguez, MDa, Joan Prats, MD, PhDa Abstract Background: The prognostic value of pretreatment lymphocyte to monocyte ratio in patients with renal cell carcinoma and, especially, in non-metastatic patients remains controversial. Methods: We conducted a PRISMA-compliant meta-analysis to systematically assess the prognostic value of LMR in patients with non-metastatic RCC. Overall survival, cancer-specific survival, and disease-free survival were analyzed. Pooled hazard ratios and 95% confidence intervals were calculated. Results: Seven studies comprising 4666 patients were included in the analysis. Unlike those observed in a previous meta-analysis, a lower lymphocyte to monocyte ratio was associated with poorer cancer-specific survival (fix-effect model, hazard ratio 3.04, 95% confidence intervals 2.05–4.51, P < .05). Heterogeneity Chi-squared value Q exp = 0. (P = .82) (I2 = 0%). However, the association between a low lymphocyte to monocyte ratio and overall survival or disease-free survival did not obtain significance. Conclusion: A lower lymphocyte to monocyte ratio implied poor cancer-specific survival in patients with non-metastatic renal cell carcinoma. Prospective studies are required to confirm our findings. Registration number: ClinicalTrials.gov (identifier: NCT04213664) Abbreviations: CI = confidence interval, CSS = Cancer-specific survival, DFS = Disease-free survival, HR = hazard ratio, IL = interleukin, LMR = Lymphocyte to monocyte ratio, OS = Overall survival, PFS = Progression-free survival, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analysis, RCC = Renal cell carcinoma, TAMs = tumor-associated macrophages. Keywords: lymphocyte to monocyte ratio, meta-analysis, prognosis, renal cell carcinoma Editor: Chien-Feng Li. 1. Introduction The authors have no funding and conflicts of interest to disclose. The datasets generated during and/or analyzed during the current study are Renal cell carcinoma (RCC) represents 2% to 3% of adult publicly available. malignant diseases. Although in the last 3 decades kidney cancer The datasets generated during and/or analyzed during the current study are is detected incidentally in most cases, a third of cases are still available from the corresponding author on reasonable request. diagnosed in locally advanced or metastatic stages, and up to Data sharing not applicable to this article as no datasets were generated or 20% to 30% of initially localized tumors will show progression analyzed during the current study. to metastasis in their evolution.[1–3] All data generated or analyzed during this study are included in this published Although the comprehensive therapeutic strategy using surgery, article [and its supplementary information files]. immunotherapy, and therapies aimed at molecular targets has a Urology Department, b Statistics Department, Consorcio Corporacion Sanitaria greatly improved the survival of these patients in recent years, a Parc Taulí, Universitat Autònoma de Barcelona, Sabadell, Spain, Catalunya, subset of them still has an unfavorable prognosis due to local Spain. ∗ recurrence or metastasis and the poor response to systemic Correspondence: Dario Garcia-Rojo, Urology Depertment, Consorcio medication. There are established clinicopathological prognostic Corporacion Sanitaria Parc Taulí, Universitat Autònoma de Barcelona, ParcTauli S/N. 08208 Sabadell, Catalunya, Spain, España (e-mail: dgarcia@tauli.cat). factors such as the existence of clinical symptoms, tumor size, stage, Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. tumor grade, histological type, or the presence of necrosis. It would This is an open access article distributed under the terms of the Creative Commons be interesting to find biological markers that would allow us to Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to provide additional prognostic information. Numerous studies download, share, remix, transform, and buildup the work provided it is properly cited. have shown that systemic inflammation plays a key role in the The work cannot be used commercially without permission from the journal. initiation and progression of different tumors.[1–23] How to cite this article: Garcia-Rojo D, Prera A, Muñoz-Rodriguez J, Oliva JC, In the tumor microenvironment, both lymphocytes and monocytes Dominguez A, Prats J. Prognostic value of lymphocyte-to-monocyte ratio previously determined to surgery in patients with non-metastatic renal cell are representatives of both host immunity and tumor aggressiveness carcinoma: a systematic review and a prisma-compliant meta-analysis. Medicine for many types of cancer. Furthermore, RCC is known to be 2021;100:3(e24152). immunogenic cancer that responds to immune therapy.[12] Received: 17 August 2020 / Received in final form: 6 November 2020 / Various systemic inflammatory biomarkers such as the Accepted: 6 December 2020 neutrophil-lymphocyte ratio, the albumin or the -C-reactive http://dx.doi.org/10.1097/MD.0000000000024152 protein have been considered to be potential prognostic markers 1 Garcia-Rojo et al. Medicine (2021) 100:3 Medicine in a wide variety of tumors. Thus, in the 2020 European Urology In each publication, information was extracted from the first Association clinical guide, it is admitted that a high neutrophil- author, year of publication, geographic location, study design lymphocyte ratio can be used as a prognostic factor in metastatic and information: sample size, mean age, distribution by sex, renal cell carcinomas, with a level of evidence type 3. Recently, LMR, the method of determining the cut-off value of LMR, many studies have shown that a lower proportion of the ratio of treatment performed, duration of follow-up, multivariate or lymphocytes to monocytes (LMR) determined in peripheral univariate analysis, the Hazard ratio (HR) and corresponding blood was closely associated with a worse prognosis in different 95% confidence intervals (CI), as well as exact p values. types of cancers, and maybe an easily available and reliable Case reports, reviews, editorials, letters, abstracts, animal-only prognostic biomarker. Furthermore, due to the limitations of and with not having access to the LMR were not considered individual studies, in most cases with a small sample of patients, eligible. and the communication of contradictory conclusions, they have Two independent reviewers identified the relevant articles in led to several meta-analysis to validate the prognostic value of duplicate by first selecting the titles and abstracts, followed by the LMR in different tumors.[1–12] full text according to the inclusion and exclusion criteria. Any We have found 3 meta-analysis that has evaluated LMR in disagreement was resolved by consensus with a third reviewer kidney tumors, but we analyzed studies in patients with both experienced in the treatment of kidney cancer. localized and metastatic tumors. Currently, the vast majority of The Newcastle-Ottawa quality assessment scale is one of the renal malignancies are detected incidentally, with clinically recommended tools to assess the quality of observational studies. localized tumors, but, as previously mentioned, a high percentage The studies where a maximum score of 9 points can be given for of patients will progress to metastatic disease. For all these each study in the categories of patient selection, comparability of reasons, we believe it is important to perform a meta-analysis to study groups and evaluation of results. High-quality studies were evaluate the prognostic value of LMR in localized renal tumors defined as those with scores higher than 7. undergoing partial or radical nephrectomy.[4,11,12] Statistical study: The raw data from each study were combined Thus, we performed a meta-analysis to systematically evaluate to obtain the combined hazard ratio and corresponding 95% the preoperative prognostic value of LMR, exclusively, in confidence intervals. The generic inverse-variance method with a patients with localized renal cell carcinoma. random-effects model was used for pooled estimates. Statistical heterogeneity among studies was assessed with I2 statistics. I2 is interpreted as the percentage of total variation across several 2. Methods studies that is attributable to heterogeneity. Larger values of I2 We performed a systematic review of the literature and a meta- indicate greater heterogeneity (50%–100%) and I2 percentages analysis according to the PRISMA (Preferred Reporting Items for below 50% are generally considered an acceptable level of Systematic Reviews and Meta-Analysis) evaluation criteria. We variability. If a P of less than .05 was observed, the studies were used the PICO method (patient, intervention, comparison, and considered to present substantial heterogeneity. The fixed-effect outcome), intending to answer the following clinical question: “Is model was used to calculate pooled results in the absence of a low value of the LMR determined before surgery a prognostic heterogeneity (I2 < 50% or P > .1). A funnel plot was performed factor in non-metastatic renal cell carcinoma?” to assess publication bias and small-study effects in the meta- All the articles analyzed were previously published studies. analyses for OS, CSS and DFS, and the Duval and Tweedie trim- That is why patient consent and ethical approval are not and-fill test was used to correct for possible publication bias. requested. All statistical tests were 2-sided and statistical significance was A comprehensive search of PubMed, ScienceDirect, and defined as P less than .05. Cochrane Database of Systematic Reviews was conducted for Statistical analysis was performed with the R 3.5.0 software (R eligible studies exploring the prognostic role of LMR in patients Core Team, 2018) and the meta library (v4.1–5; Schwarzer, with localized kidney tumors undergoing partial or radical Guido, 2019). nephrectomy from January 1965 to December 2019. The terms The study was approved by the ethical research committee of Search included: “lymphocyte-monocyte ratio,” “kidney can- our center (Consorcio Corporacion Sanitaria Parc Taulí), cer,” “prognosis.” (identifier: 2019/679) and is registered at ClinicalTrials.gov Inclusion Criteria: Any observational study (cross-sectional, (identifier: NCT04213664). case-control, longitudinal with cross-sectional data) was includ- ed. Articles about patients older than 18 years, with localized 3. Results renal tumors that underwent partial or radical nephrectomy, with histopathologically confirmed neoplasms, who had access to the A total of 29 studies were identified by searching PubMed, full text and without language limitation, were being discussed. ScienceDirect, and Cochrane Database of Systematic Reviews. Studies reflected the hazard ratios (HR) and corresponding They were selected to be read in full 18. The selection process 95% confidence intervals (CI), in which overall survival (OS), yielded only 7 studies that met the selection criteria for cancer-specific survival (CSS) and disease-free survival (DFS). If performing the meta-analysis. These 7 studies provided informa- data forms from both univariate and multivariate analyzes were tion on 4666 patients with non-metastatic renal cell carcinoma. available in the articles, data from the multivariate analysis was The flowchart identifying the eligible studies is depicted in extracted for the cluster analysis. OS was defined as the interval Figure 1. The studies were published between 2014 and 2019, 4 from the date of surgery in the primary tumor until death. CSS of them reported by groups from China, 2 Austrians, and 1 was defined as the interval from the date of surgery in the primary Korean. tumor to death for RCC. DFS was defined as the interval from the The cutoff values for a low LMR were inconsistent, ranging date of surgery in the primary tumor to local, regional, or distant from 2.5 to 5. The cut-off value was determined using different recurrence. methods: ROC análisis curve in 4 studies, 25th percentile in 2 2 Garcia-Rojo et al. Medicine (2021) 100:3 www.md-journal.com Figure 1. PRISMA flow diagram of the systematic literature search. (PRISMA, preferred reporting items for systematic reviews and meta-analysis). studies or máximum survival difference in 1 study. More Because of the results, it was not deemed necessary to supplement information on the main characteristics are summarized in the study with any statistical test. Tables 1 and 2. However, the association between low LMR and OS (fixed Quality scores according to the New Castle-Ottawa scale for effects model, HR 0.86, CI 95% 0.68–1.08, P > .05) and DFS all included studies were 8 out of 9, suggesting that all included (fixed effects model, HR 0.77 95%, CI 0.62–0.97, P > .05) did studies were eligible for meta-analysis. (Table 3) not obtain statistical significance. (Fig. 2) Analyzing these 7 studies evaluating the prognostic value of LMR in patients with non-metastatic RCC, in 5 they reported the 4. Discussion results of OS (3099 patients), in 4 results of CSS (2821 patients), and in 5 results of DFS (3660 patients). Tumor stage using TNM classification, degree of cell differentia- In summary, non-metastatic CRC patients with a low LMR tion, tumor size, histological type, and the presence of were associated with a lower CSS (fixed effects model, HR 3.04, tumor necrosis are known as prognostic factors established in 95% CI 2.05–4.51, P < .05). In the analysis of heterogeneity, we RCC. Despite trying the most individualized treatment obtained a value of I2 = 0% (homogeneity) (Fig. 2). The funnel and follow-up possible, it is important to identify possible plot of the assessment of publication bias was symmetric (Fig. 3), biomarkers that help clinicopathological parameters to make this which suggested that our meta-analysis is robust and reliable. decision.[1–23] Table 1 Characteristics of the studies subjected to meta-analysis. Study No. Mean Female Cut-off value Determine the Median followup [year] Country Patients Age [yrs] [%] of low LMR cut-off value [months] Hutterer et al [2014] Austria 678 65.0 40.3 <3 ROC análisis curve 44 [0–130] Lucca et al [2015] Austria 430 65.5 40.2 < 2.5 Máximum survival difference 40 [17–73] Chang et al [2016] China 430 56 27.7 < 3.25 25th percentile 66 [63–70] Xia et al [2016] China 985 55 42.6 <3 25th percentile 58 [3–60] Chen et al [2017] China 592 56.3 37.3 < 3.3 ROC análisis curve 69.2 [1–151] Elghiaty et al [2018] Korea 1137 56 28 <5 ROC análisis curve 65 [43–91] Chen et al [2019] China 414 56.3 37.9 < 3.3 ROC análisis curve 69.2 [1–151] 3 Garcia-Rojo et al. Medicine (2021) 100:3 Medicine Table 2 HRs [95% CI] showing the association between LMR and prognosis with localized renal cell carcinoma. Study [yr] OS CSS DFS Hutterer et al [2014] 1.373 [0.929–2.031] 2.332 [1.100–4.942] 1.586 [0.936–2.690] Lucca et al [2015] NR NR 2.44 [1.27–4.67] Chang et al [2016] 0.336 [0.194–0.584] NR 0.464 [0.282–0.765] Xia et al [2016] 0.26 [0.16–0.41] NR 0.24 [0.16–0.36] Chen et al [2017] 3.406 [1.670–6.946] 2.961 [1.416–6.190] NR Elghaty et al [2018] NR 4.06 [1.55–10.59] 2.17 [1.19–3.97] Chen et al [2019] 3.417 [1.670–6.972] 3.416 [1.596–7.314] NR [LMR = lymphocyte-to-monocyte ratio, HR = hazard ratio, IC = confidence interval, NR = not reported, OS = overall survival, CSS = cancer specific survival, DFS = disease-free survival]. Different biomarkers have recently been determined as a between CA 15–3, CA 125 and b-2 microglobulin serum values potentials prognostic factors in patients treated for RCC. Urinary and tumor size, Fuhrman grade, presence of lymph node, and Raf Kinase Inhibitor Protein, a key regulator of cell signaling, visceral metastases. CSS was significantly decreased for patients already described in several cancer types as a metastasis with high levels of CA 15–3, CA 125, and b-2 microglobulin. At suppressor, enabled a highly accurate prediction of Cancer- multivariate analysis only age, the presence of visceral metasta- specific survival and Progression-free survival.[17] Pentraxin-3 ses, and high levels of CA 15–3 were independent adverse belongs to the pentraxine family, innate immune regulators prognostic factors for CSS.[21] involved in angiogenesis, proliferation and immune escape in Various studies have demonstrated the prognostic significance cancer. Higher Pentraxin-3 serum levels were observed in of a low LMR in both localized and metastatic RCC.[2–12] Thus, a patients with higher Fuhrman grade, lymph node, and visceral low LMR is correlated with tumoral patients with a high metastases. Patients with higher Pentraxin-3 levels also showed histological grade, larger size, higher tumor stage, lower OS, significantly lower cancer specific survival rates.[18] Glucose-6- lower CSS, lower recurrence-free survival, and lower PFS.[2–12] phosphate isomerase, also known as phosphoglucose isomerase, There are 2 meta-analysis where the prognostic value of LMR was initially identified as the second glycolytic enzyme that has been investigated in urological tumors and another in renal catalyzes the interconversion of glucose-6-phosphate to fructose- carcinoma. Patients with both localized and metastatic disease 6-phosphate. Later studies demonstrated that Glucose-6-phos- have been included in all 3 studies. And the patients were treated phate isomerase was the same as the autocrine motility factor, with either surgery, systemic therapy, or both. All 3 studies and that it mediates its biological effects through the interaction showed lower overall survival and specific cancer in patients with with its surface receptor. Lucarelli et al (2015) demonstrated that low LMR.[4,11,12] Glucose-6-phosphate isomerase was an independent adverse But to date, we have found no meta-analysis that specifically prognostic factor for CSS and progression free survival (PFS).[19] focuses on investigating the prognostic value of LMR in patients The renoprotective antiaging gene, aKlotho, has recently been with localized kidney tumors. found to work as a tumor suppressor. Gigante et al (2015) In the present study, we identified 7 studies that involved 4666 observed statistically significant differences resulted between patients, and we investigated the prognostic value of LMR serum aKlotho levels and tumor size, Fuhrman grade, and clinical exclusively in patients with localized renal cell carcinoma who stage. CSS and PFS were significantly shorter in patients with had undergone total or partial nephrectomy. Unlike those lower levels of aKlotho.[20] Lucarelli et al (2014), in a prospective observed in the previous meta-analysis, our study showed that a study, observed statistically significant differences resulted low LMR, determined in peripheral blood prior to surgery, was Table 3 The Newcastle-Ottawa Scale quality assessment of the included studies. Selection Comparation Outcome Demonstration Demonstration outcome of that outcome of Was follow-up Representativeness Selection interest was interest was long enough Adequacy of the of the Ascertainment not present not present Assessment for of follow exposed nonexposed of at start that at start of outcomes up of Study [Year] cohrt cohort exposure of study of study outcome to occur cohorts Total ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Hutterer et al [2014] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Lucca et al [2015] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Chang et al [2016] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Xia et al [2016] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Chen et al [2017] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Elghiaty et al [2018] 8 ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ Chen et al [2019] 8 ∗ Represents a score for the corresponding item. 0 Does not represent a score for the corresponding item. 4 Garcia-Rojo et al. Medicine (2021) 100:3 www.md-journal.com Figure 2. The forest plot of the relationship between the LMR and OS, CSS, and DFS in non-metastatic renal cell carcinoma. [CSS = cancer-specific survival, DFS = disease-free survival, LMR = lymphocyte-to-monocyte ratio, OS = overall survival]. associated with poorer CSS, but not with lower OS or DFS in (2019) demonstrated in tumor tissue that a higher proportion of patients with non-metastatic renal cell carcinoma.[4,11,12] regulatory T cells lymphocytes were associated with poor Tumor-infiltrating immune cells are crucial for the clinical outcome in patients with RCC. Conversely, resting mast cells outcome of RCC, as they regulate cancer progression. Zu et al and monocytes were associated with a favorable prognosis in 5 Garcia-Rojo et al. Medicine (2021) 100:3 Medicine Figure 3. The funnel plot of the Begg test for the publication bias assessment of the synthesized HR assessing the prognostic value of pretreatment LMR for CSS in non-metastatic renal cell cancer. [CSS = Cancer-specific survival, HR = Hazard ratio, LMR = lymphocyte-to-monocyte ratio]. patients with RCC.[22] On the other hand, Tumor-infiltrating are impaired.[15] These metabolic changes induce the increased lymphocytes, particularly CD8(+) T cells, could be a manifesta- production of several oncometabolites such as kynurenine that tion of antitumor immunity. Nakano et al (2001) clinicopath- modify the inflammatory infiltrate.[16] ologically analyzed the biological significance of tumor- The exact mechanisms responsible for the correlation between infiltrating lymphocytes in 221 patients with RCC without low LMR and poor outcome in RCC are unclear. Various preoperative treatments. More abundant infiltration of tumor hypotheses help explain these observations. The inflammatory tissue not only by CD8(+) but also CD4(+) T cells was associated cell response secondary to tumor proliferation could cause the with shorter survival of the patients, because of the positive production and release of various inflammatory cytokines and correlation between the number of lymphocytes and representa- mediators, ultimately promoting tumor invasion, migration, tive tumor grade factors. This suggests that immune cell reactions metastasis, and progression. Lymphocytes, especially tumor- are more pronounced as the tumor grade/biological malignancy infiltrating lymphocytes, play a critical role in cell-mediated progresses, probably because of increased antigenicity of tumor antitumor. Low lymphocyte counts may, therefore, result in an cells. The same group analyzed the proliferative activity of CD8 insufficient immunological reaction, which would lead to poorer (+) T cells that infiltrated in tumor cell nests, which could also survival in a number of cancer immune response. Monocytes, reflect antitumor immunity. Higher labeling index of Ki-67, a especially those differentiated into tumor-associated macro- proliferation-associated antigen, among CD8(+) T cells in contact phages (TAMs), are also involved in tumorigenesis. Several to tumor cells was associated with a longer survival. This data in studies reported that the absolute monocyte count was associated human renal cell carcinoma suggest that infiltration of tumor with survival in patients with different types of cancer. However, tissue by T cells itself does not denote the efficacy of antitumor the exact mechanisms underlying the role of monocytes in tumor immunity because of its dependence on the biological malignancy progression have not been well elucidated yet. The link between of tumor cells, but infiltration of tumor tissue by CD8(+) T cells monocytes and TAMs may explain how monocytes are involved bearing more pronounced proliferative activity could reflect in the inflammatory tumor response. The circulating level of effective antitumor immunity. This concept is important for monocytes may reflect a substrate for the formation or presence immunotherapy of RCC treatment.[23] of TAMs. TAMs are sensitive to the chemotactic effect of the Recent studies suggest that an altered metabolism is involved in tumor microenvironment where there are cytokines and chemo- the development of RCC, and in this tumor many altered genes kines secreted by monocytes. Furthermore, the interaction play a fundamental role in controlling cell metabolic activities. between TAMs and cancer cells is capable of promoting tumor Thus, RCC is characterized by a reprogramming of energetic angiogenesis, migration, invasion, and depressing antitumor metabolism. In particular the metabolic flux through glycolysis is immunity, which ultimately leads to tumor progression and partitioned,[13,14] and mitochondrial bioenergetics and OxPhox worse prognosis in neoplastic patients.[2–12] 6 Garcia-Rojo et al. Medicine (2021) 100:3 www.md-journal.com Additionally, there is another hypothesis that may also explain Author contributions the role of monocytes in tumor progression. Thus, monocytes Administrative support: none infiltrating the tumor could release many soluble factors, such as Concept and design of the study: Dario Garcia-Rojo. interleukin (IL) -1, IL-6, IL-10, and tumor growth factor-alpha, Conceptualization: Dario Garcia-Rojo, Angel Prera, Jesus and it has been well studied that these factors play an important Muñoz-Rodriguez, Arturo Dominguez. role in promoting neo-angiogenesis, tumor invasion, and Critical revision of the manuscript content: Angel Prera, Jesus migration, and correlates with an unfavorable prognosis in Muñoz-Rodriguez, Arturo Dominguez. several malignant tumors. Furthermore, monocytes may contain Data acquisition: Dario Garcia-Rojo, Angel Prera, Jesus Muñoz- mitogens that can impair lymphocyte-dependent anti-tumor Rodriguez. defense in suppressing anti-tumor immunity. LMR represents the Data analysis and interpretation: Dario Garcia-Rojo, Angel balance between the immune status of the host and the degree of Prera, Jesus Muñoz-Rodriguez, Arturo Dominguez. tumor progression. However, the reason why LMR is altered in Data curation: Dario Garcia-Rojo. cancers has not been fully identified so far. One possibility is that Drafting of the manuscript: Dario Garcia-Rojo. there may be an inflammatory-immune imbalance in the genesis Formal analysis: Dario Garcia-Rojo, Angel Prera, Jesus Muñoz- of cancer, in which the induction of inflammatory immune cells, Rodriguez, Joan Carles Oliva, Arturo Dominguez. such as lymphocytes or monocytes, are influenced by factors Methodology: Dario Garcia-Rojo. associated with the tumor. Moreover, as previously mentioned, Statistical analysis: Joan Carles Oliva. monocytes can restrict the mitogen and the lymphocyte Supervision: Joan Prats. proliferative response antigen, which can also contribute to the Validation: Angel Prera, Jesus Muñoz-Rodriguez, Arturo alteration of LMR. Therefore, we can speculate that the LMR Dominguez. could reflect the state of antitumor immunity and predict the Writing – original draft: Dario Garcia-Rojo. prognosis of patients with kidney cancer. And in this way, the LMR could serve a novel prognostic predictor of survival in patients with non-metastatic RCC and may be incorporated in References any predictive prognostic model. Furthermore, LMR is an easy [1] European Association of Urology. Guidelines. Renal cell carcino- and inexpensive parameter to determine.[2–12] ma.2019 update (Accessed July 31, 2020). Available at: http:// However, to date, LMR has not been recommended as a uroweb.org/guideline/renal-cell-carcinoma/. [2] Grimes N, Tyson M, Hannan C, et al. A systematic review of the prognostic factor by the European Association of Urology in the prognostic role of hematologic scoring systems in patients with renal cell clinical guidelines for renal carcinoma, since most of the evidence carcinoma undergoing nephrectomy with curative intent. Clin Genito- supporting the prognostic value of LMR in these tumors come urin Cancer 2016;14:271–6. from retrospective studies, with small sample size.[1] [3] Wang X, Su S, Guo Y. The clinical use of the platelet to lymphocyte ratio Several limitations we can observe in our meta-analysis. First, and lymphocyte to monocyte ratio as prognostic factors in renal cell carcinoma: a systematic review and meta-analysis. Oncotarget 2017; the included studies were designed retrospectively and in 3 of the 7, 8:84506–14. they represented the experience of a single-center, which can lead to [4] Li J, Cheng Y, Ji Z. Prognostic value of pretreatment lymphocyte-to- bias. Second, most of the studies analyzed had a small sample size. monocyte ratio in patients with urologic tumors: A PRISMA-compliant Third, in some of the studies analyzed, the HR and 95% CI were meta-analysis. Medicine (Baltimore) 2019;98:e14091. [5] Hutterer GC, Stoeckigt C, Stojakovic T, et al. Low preoperative obtained from survival curves, which may cause some statistical lymphocyte-monocyte ratio (LMR) represents a potentially poor error. Fourth, the LMR cut-off value was not uniform across prognostic factor in nonmetastatic clear cell renal cell carcinoma. studies. Fifth, the HR and 95% CIs in some studies corresponded Urologic oncology: seminars and original investigations 2014;32: to a univariate análisis. Other inconsistent values in aspects such as 1041–8. the proportion of sex, age, geographic areas, and patient follow- [6] Lucca I, de Martino M, Hofbauer SL, et al. 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Preoperative albumin to globulin ratio that a low LMR, determined in peripheral blood before surgery, predicts survival in clear cell renal cell carcinoma patients. Oncotarget was associated with poorer CSS, but not with lower OS or DFS in 2017;8:48291–302. patients with non-metastatic renal cell carcinoma, unlike the [10] Elghiaty A, Kim J, Jang WS, et al. Predictive value of preoperative results observed in the 3 previous meta-analysis. However, more monocyte-lymphocyte ratio among patients with localized clear renal cell prospective, heterogeneous, and larger sample studies are required carcinoma of 7cm on preoperative imaging. Medicine (Baltimore) 2018;97:e13433. to further confirm our findings before it can be applied for daily [11] Chen Z, Wang K, Lu H, et al. 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