Abstract
Introduction & Objectives:
In systemic therapy trials, a decreasing neutrophil-to-lymphocyte ratio (NLR) after treatment for metastatic renal cell carcinoma (RCC) has been associated with improved oncologic outcomes. Paradoxically, for patients with localized RCC treated with upfront surgery the opposite effect has been reported. We thus aimed to evaluate NLR dynamics on localized RCC recurrence.
Methods:
Treatment naïve patients with localized RCC managed surgically between 2005-2020 were included. Preoperative NLR was calculated within six-weeks prior to surgery and postoperative NLR was calculated between four- to twelve-weeks after surgery. Patients were followed for disease recurrence, noting metastatic sites and postoperative infections. Cox regression were used to determine whether the relative change in postoperative NLR was associated with metastasis-free survival (MFS) and cancer-specific survival (CSS), adjusted for preoperative NLR.
Results:
In the cohort of 3310 patients, 996 (30%) had postoperative NLR available. These patients generally had more advanced disease, with 100 developing metastases and 38 dying from kidney cancer. Median MFS follow-up was 4.4 years. Decreasing two-month postoperative NLR was associated with non-statistically significant worse MFS and CSS (HR 0.79, 95% 0.50, 1.24, p=0.3; HR 0.83, 95% C.I. 0.40, 1.73; p=0.6). On sensitivity analysis, across all NLR measurements, with NLR as a time-dependent covariate, results were similar, with a declining NLR associated with adverse MFS (HR 0.85, 95% CI 0.69, 1.30, p-value = 0.10), though not meeting conventional levels of significance.
Conclusion:
In higher-risk localized RCC patients, postoperative NLR is not suitable as a biomarker for predicting recurrences.
Keywords: renal cell carcinoma, nephrectomy, neutrophil, lymphocyte, infection, oncological outcomes
Microabstract:
Evaluating the postoperative neutrophil-to-lymphocyte (NLR) ratio following nephrectomy for localised renal cell carcinoma and oncological outcomes. A prospectively managed database of 996 patients operated between 2005 - 2020. There was no association between NLR dynamics and disease recurrence. Therefore, there is no clinical role for monitoring the NLR in patients after renal surgery.
INTRODUCTION
Renal cell carcinoma (RCC) is an aggressive genitourinary malignancy, causing an estimated 13,780 deaths in the United States in 20211. For localized RCC, surgery remains the gold standard of therapy, however, many patients subsequently experience local recurrence or distant metastases2. Nomograms predicting recurrence after surgery focus on clinicopathological variables, however multiple studies have shown that preoperative inflammatory parameters may also predict outcomes after surgery3,4.
The preoperative neutrophil-to-lymphocyte ratio (NLR) has been associated with oncological outcomes for RCC surgery in the metastatic and localized setting5-7. However, few studies have characterized the natural history of NLR dynamics following surgery. If the NLR reflects the systemic immune response to the tumor, then in theory, a tumor-driven immune-response should abate postoperatively. Further, we could expect to see a persistently elevated NLR in patients that subsequently experience disease recurrence or progression. This has been shown in metastatic RCC, where a decreasing NLR after commencing immune checkpoint blockade is associated with improved progression-free survival and objective response rates8. In the only study to date assessing postoperative NLR changes in localized RCC, the opposite effect was found, whereby a low postoperative NLR conferred adverse metastasis-free survival (MFS)9.
Postoperative NLR may be affected by factors associated with inflammation, notably surgery itself and postoperative infections. Finally, it is unknown whether there is any association between NLR dynamics and the site of metastasis. Therefore, we aimed to characterize NLR dynamics, accounting for postoperative infections, and determine whether there is an association between perioperative changes in NLR and oncological outcomes, including metastasis to different sites.
METHODS
After obtaining Institutional Review Board approval, we reviewed our prospectively-maintained nephrectomy database for consecutive cases of treatment-naïve patients with localized RCC managed surgically between 2005 and 2020. Clinicopathological details, complete blood counts and infection data were obtained for all patients.
Patients were followed for disease recurrence, noting subsequent metastatic sites and postoperative infections. Metastatic sites were recorded as either bone, node, viscera and other sites. Postoperative infection status was defined as the presence or absence of a positive culture up to three-months after nephrectomy.
The NLR was calculated by dividing the neutrophil count by lymphocyte count from the same complete blood count. Preoperative NLR was calculated within six weeks prior to surgery, selecting the value closest to the date of surgery. We used a landmark of 12-weeks for this study, where postoperative NLR was calculated between four to twelve weeks after surgery, selecting the value closest to eight weeks after surgery. This interval represents the typical window of postoperative follow up and avoids capturing the systemic inflammatory response seen immediately after surgery.
We identified 3669 patients with localized RCC and no pre-operative systemic treatment who were treated with nephrectomy between 2005 and 2020 with available preoperative NLR measurements. We excluded 195 patients identified as having T0 disease on pathology, 6 patients with incomplete data pertaining to covariates used in our models and 158 patients with less than 12 weeks of follow up after surgery, which was necessary to define postoperative NLR and determine postoperative infection status.
Among the remaining 3310 patients available for analysis, 996 (30%) had two-month postoperative NLR values available. To assess whether there are differences between patients with available two-month postoperative NLR and those without, we compared patient characteristics based on whether patients had postoperative NLR available.
For our primary aim, we were interested in whether the change in NLR was associated with kidney cancer death or metastasis beyond 12-weeks after surgery. Due to the limited number of events for the outcome of kidney cancer death, we used a Cox proportional hazard model with the predictor of postoperative NLR, with preoperative NLR as the sole covariate. For the outcome of metastasis, we used two models, additionally adjusting for age, gender, tumor size, high tumor stage on pathology (pT1-pT2b vs pT3a-pT4) and positive margin status. Additionally, all NLR values were calculated longitudinally up to disease recurrence or last follow-up, and we created a figure depicting all NLR measurement after surgery, rather than just focusing on the two-month postoperative NLR.
To assess whether the relationship between the change in NLR and metastasis differs based on postoperative infection status within 90-days of surgery, a Cox proportional model was used with an interaction term between postoperative NLR and postoperative infection and adjusted for the same covariates as mentioned above. We then wished to create a final model incorporating both change in NLR and postoperative infection, which would be based on whether the interaction term was significant. In particular, if there was a significant interaction between postoperative NLR and postoperative infection, we would assess the association between change in NLR and metastasis separately based on infection status. Otherwise, if there was no significant interaction, we would assess the association between change in NLR and metastasis, additionally adjusting for postoperative infection status in addition to the previously specified covariates.
As a secondary aim, among patients who developed a metastasis, we visualized the distribution of preoperative and postoperative NLR values based on the site of metastasis. We created a ridge plot for the distribution of NLR for four different sites of metastasis: bone, visceral, nodal, and other.
As our hypotheses were related to the relative, not the absolute, change in NLR, the log transformation of NLR was used in all the aforementioned models. All statistical analyses were conducted using R version 4.0.1.
RESULTS
From 3310 patients, 996 (30%) patients had postoperative NLR values available within the specified window. Patients with available postoperative NLR values had larger, higher stage, higher grade, more frequently necrotic tumors that were more often associated with positive lymph nodes. Hence patients with postoperative NLR measured had worse disease characteristics than patients without available postoperative NLR. Although we found evidence of differences in preoperative neutrophil, lymphocyte and thus NLR between groups, these differences were small (differences in median and quartiles were ±0.2). All other patient demographics were similar between the two groups (Table 1a and 1b). Among those with available postoperative NLR, 100 patients developed a metastasis and 38 patients died from kidney cancer. The median follow-up time among metastasis-free survivors was 4.4 (IQR 2.4, 7.1) years from nephrectomy.
Table 1a.
Patient characteristics stratified by whether patients had available postoperative NLR.
Results are presented as median (quartiles) and frequency (%).
| Characteristic | Unavailable Postoperative NLR N = 2,314 |
Available Postoperative NLR N = 996 |
p-value |
|---|---|---|---|
| Age at surgery in years | 61 (52, 68) | 61 (53, 69) | 0.2 |
| Male | 1,523 (66%) | 680 (68%) | 0.2 |
| Race | 0.068 | ||
| White | 1,939 (84%) | 866 (87%) | |
| Black | 126 (5.4%) | 50 (5.0%) | |
| Asian | 107 (4.6%) | 43 (4.3%) | |
| Other | 53 (2.3%) | 14 (1.4%) | |
| Unknown | 89 (3.8%) | 23 (2.3%) | |
| Body Mass Index | 29.2 (26.0, 33.3) | 29.4 (26.3, 33.4) | 0.4 |
| Unknown | 12 | 15 | |
| Preoperative Neutrophil | 4.3 (3.4, 5.3) | 4.4 (3.5, 5.5) | 0.012 |
| Preoperative Lymphocyte | 1.7 (1.3, 2.1) | 1.6 (1.3, 2.0) | 0.003 |
| Preoperative NLR | 2.5 (1.9, 3.4) | 2.7 (2.0, 3.7) | <0.001 |
| ASA Score | 0.2 | ||
| 1 | 39 (1.7%) | 11 (1.1%) | |
| 2 | 887 (38%) | 355 (36%) | |
| 3 | 1,338 (58%) | 605 (61%) | |
| 4 | 49 (2.1%) | 24 (2.4%) | |
| Unknown | 1 | 1 |
Table 1b.
Disease and postoperative characteristics stratified by whether patients had available postoperative NLR.
Results are presented as median (quartiles) and frequency (%).
| Characteristic | Unavailable Postoperative NLR N = 2,314 |
Available Postoperative NLR N = 996 |
p-value |
|---|---|---|---|
| Partial Nephrectomy | 1,747 (75%) | 661 (66%) | <0.001 |
| Tumor Size | 3.3 (2.3, 4.9) | 4.0 (2.5, 6.4) | <0.001 |
| High Grade | <0.001 | ||
| High | 850 (46%) | 472 (55%) | |
| Low | 1,014 (54%) | 383 (45%) | |
| Unknown | 450 | 141 | |
| Tumor Stage on Pathology | <0.001 | ||
| T1 | 1,746 (75%) | 615 (62%) | |
| T2 | 95 (4.1%) | 40 (4.0%) | |
| T3 or 4 | 473 (20%) | 341 (34%) | |
| Nodal Stage on Pathology | <0.001 | ||
| N0 | 523 (23%) | 359 (37%) | |
| N1 | 9 (0.4%) | 16 (1.6%) | |
| N2 | 3 (0.1%) | 18 (1.8%) | |
| NX | 1,720 (76%) | 589 (60%) | |
| Unknown | 59 | 14 | |
| Positive Margins | 0.8 | ||
| Negative | 2,204 (95%) | 946 (95%) | |
| Positive | 110 (4.8%) | 50 (5.0%) | |
| Postoperative Neutrophil | -- | 4.4 (3.5, 5.5) | |
| Unknown | 2,314 | 0 | |
| Postoperative Lymphocyte | -- | 1.6 (1.2, 2.0) | |
| Unknown | 2,314 | 0 | |
| Postoperative NLR | -- | 2.6 (2.0, 3.8) | |
| Unknown | 2,314 | 0 |
We evaluated the association between preoperative NLR and oncologic outcomes, and similar to many prior studies, we found that higher preoperative NLR was associated with adverse MFS and CSS on univariable analysis (HR 2.37; 95% CI 1.64, 3.43, p<0.001 and HR 2.89; 95% CI 1.58, 5.28, p<0.001, respectively). For example, the 5-year predicted probability of metastasis is 9% and 12% for patients with preoperative NLR values of 2.7 and 3.5, respectively.
Figure 1a highlights the distribution of all post-operative NLR measurements for patients in our cohort, with Figure 1b additionally excluding measurements for patients who experienced postoperative infections within 90-days of surgery. When assessing the association between the change in NLR and outcomes, a decrease in postoperative NLR at the two-month interval was associated with non-statistically significant worse MFS and CSS (HR 0.79, 95% CI 0.50, 1.24, p-value = 0.3 and HR 0.83, 95% CI 0.40, 1.73, p-value = 0.6, respectively). We did not see a significant interaction between change in NLR and postoperative infection (interaction p-value = 0.7), and in our final model after additionally adjusting for postoperative infection, results remained similar (HR 0.97, 95% CI 0.60, 1.54, p-value = 0.9).
Figure 1.
Line-plot of all postoperative NLR measurements up until metastasis or last follow-up in (a) all patients, (b) excluding patients who developed infection within 90-days of surgery. Blue points represent last NLR measurements in patients who developed metastasis during the follow-up period, and red points represents last NLR measurements in patients who did not develop metastasis at last follow-up. Figures excludes patients with <6 weeks to metastasis or last follow-up, and NLR measurements >20.
On post-hoc analysis, we assessed the association between all NLR measurements and metastasis using a multivariable Cox proportional hazard models with NLR as a time dependent covariate and adjusted for all other covariates in our primary analysis. Here, a decrease in NLR was associated with worse MFS (HR 0.85, 95% CI 0.69, 1.03, p-value = 0.10), which is illustrated in Figure 2 where the predicted risk of metastasis for a patient with an NLR value of 2.7—corresponding to the lower quartile—is higher compared to a patient with an NLR value of 5, corresponding to the median, while all other continuous covariates are set to the mean and categorical covariates set to the mode. Additionally, we carried out a post-hoc analysis evaluating whether the association between post-operative NLR and metastasis differed based on whether patients had low or high stage disease on pathology. To this end, we used a Cox proportional model with an interaction term between postoperative NLR and high stage on pathology and adjusted for the same covariates as in our final model. We did not see evidence that the association between post-operative NLR and metastasis-free survival differed based on high stage on pathology (interaction p-value = 0.4).
Figure 2.
Predicted probability of metastasis for NLR value of 2.7 (red) and 5 (blue) from multivariable cox regression with NLR as a time-dependent covariate.
Table 2 presents the breakdown of metastasis type, where the majority are visceral metastases, and of note, 16 patients developed metastasis that would fit within multiple categories. Figure 3 displays the distribution of preoperative and postoperative NLR based on metastasis type among patients with available postoperative NLR, where generally speaking, we see a larger range of NLR values for patients with visceral or bone metastasis, compared to nodal metastasis. Supplementary Figure 1 shows the distribution of preoperative NLR for all metastasis types after additionally including patients without postoperative NLR available, where patients with nodal metastasis now have a similar distribution compared to the other metastatic sites.
Table 2.
Frequency (proportion) of metastasis type among patients who developed metastasis.
| Characteristic | Unavailable Postoperative NLR N = 110 |
Available Postoperative NLR N = 100 |
|---|---|---|
| Number of Metastases | ||
| 1 | 97 (88%) | 84 (84%) |
| 2 | 10 (9.1%) | 15 (15%) |
| 3 | 3 (2.7%) | 1 (1.0%) |
| Bone Metastases | 24 (22%) | 16 (16%) |
| Nodal Metastases | 17 (15%) | 21 (21%) |
| Visceral Metastases | 78 (71%) | 77 (77%) |
| Other Metastases | 7 (6.4%) | 3 (3.0%) |
Total percentage among metastatic sites exceeds 100% as some patients presented with more than one site of metastasis.
Figure 3.
Distribution of preoperative (within 6-weeks prior to surgery) and postoperative (4-12 weeks after surgery) NLR based on metastatic site*.
*As only three patients had an “Other” site metastasis, this site is not shown in the figure
DISCUSSION
Our longitudinal study, characterizing the natural history of the NLR dynamics after nephrectomy, does not demonstrate an association between postoperative NLR and clinical outcomes.
In 2012, Ohno et al. published a study of 250 patients measuring NLR preoperatively, three months postoperatively and at the time of recurrence. The authors reported that patients who recurred had a high preoperative NLR and a low three-month postoperative NLR9. This paradoxical finding has not been tested externally, and is especially unexpected as studies of other inflammatory markers that are elevated after surgery are associated with adverse outcomes10. Furthermore, despite the patients that experienced a recurrence having a lower three-month NLR, thereafter Ohno showed that at the time of recurrence their NLR was again elevated back to preoperative levels. Li et al. described a similar perioperative phenomenon for overall survival after surgery in stage I-III colon cancer11. Combined, these findings suggest that acute postoperative systemic inflammatory dynamics may have downstream oncological implications. While our study found that a postoperative decline in NLR at two months, as well as a time-dependent covariate was associated with adverse MFS, neither analyses met conventional levels of statistical significance, with wide confidence intervals.
Potentially, an elevated NLR that resolves with macroscopic resection could represent a tumor driven systemic immune response, as distinct from a persistently elevated NLR. Indeed, Ohno’s observation of an elevated NLR at the time of recurrence suggests that these more aggressive tumors generate a systemic immune response with disease resection and progression. An elevated preoperative NLR has been linked to oncological outcomes in other solid tumors, including genitourinary cancers12. Interestingly, an elevated preoperative NLR is also associated with complications after non-oncological surgeries13. Furthermore, in localized RCC, preoperative NLR has been associated with adverse overall survival but not disease specific outcomes, suggesting that the NLR is a non-specific prognosticator14. Therefore, rather than characterizing a tumor driven-immune response, a stably elevated NLR may reflect baseline physiological inflammatory states.
A large retrospective SEER database cohort study described an association between perioperative infections (which invariably increase the NLR) and improved cancer-specific outcomes15. Therefore, we wanted to ascertain whether improved outcomes from an elevated postoperative NLR were driven by postoperative infections. Herein, the association between NLR and clinical outcomes did not differ based on infection. Although our methodology may not have captured all patients with minor infections treated empirically without an initial culture, our findings suggest that the NLR paradox reported by Ohno cannot be explained by postoperative infections.
Studies have evaluated treatment related changes on the NLR in metastatic RCC managed both surgically or with systemic therapy. Mano et al. explored the role of NLR changes after cytoreductive nephrectomy for sarcomatoid RCC, a variant known for its aggressive phenotype16. Using three categories for differences in NLR (minimal change, increase and decrease), they found no association between NLR change and outcome. The authors suggest that the natural history of NLR changes with surgery may vary between localized and cytoreductive surgery, as residual macroscopic disease remains after a cytoreductive nephrectomy. In the systemic therapy setting, a 6-week decrease in NLR is associated with improved PFS for both targeted therapy and immunotherapy8,17. Therefore, while an elevated pretreatment NLR confers adverse outcomes for both localized and metastatic RCC, studies report that the favorable directional change in NLR six-weeks after treatment differs between localized and metastatic RCC.
This study is the first to explore whether NLR is associated with metastatic sites in RCC. Due to the extensive number of unique metastatic sites and the relatively few number of metastatic events, a broad classification of bone, lymph nodes, viscera and other sites was used. Although we did not see a clear difference in preoperative NLR based on the site of metastasis, there was a bimodal distribution of postoperative NLR for bone metastasis, perhaps due to a higher proportion of bone metastases being symptomatic. A multi-cancer study, not including RCC, noted that bone metastases had a slightly higher NLR than other metastases, and synchronous metastases involving bones and other sites had a significantly higher NLR18. We were not powered to assess whether increased postoperative NLR for bone metastasis was due to increased rate of symptomatic metastases or other factors. While this may be an interesting study to undertake across a cohort with RCC bone metastases, the clinical utility remains unclear.
Our study is limited by the nonuniform use of complete blood counts postoperatively, with a greater proportion of patients with higher-risk disease being tested. Of note, this sample bias differs markedly from Ohno et al’s publication, which was instead limited by excluding a large percentage of high-risk localized patients, due to them receiving adjuvant treatment. Indeed, our postoperative NLR results are strengthened by all patients remaining off systemic treatment until disease recurrence. Finally, as Figure 1 illustrates, the postoperative NLR is highly variable and therefore interpretation of a single measurement warrants caution.
CONCLUSION
A decrease in two-month postoperative NLR was only weakly associated with an adverse MFS and not statistically significant. While some clinicopathological characteristics help to inform surveillance strategies for metastases, the postoperative NLR does not provide clinically useful insights. Therefore, the postoperative NLR is not a suitable biomarker for predicting recurrence.
Supplementary Material
Clinical practice points.
A small number of clinical studies have analyzed the systemic immune response following surgical resection of RCC. The preoperative neutrophil-to-lymphocyte ratio (NLR) has been associated with oncological outcomes for RCC, however, few studies have explored NLR dynamics after surgery and the association with disease recurrence. In 2012, Ohno et al reported that a reduced NLR after renal surgery was associated with adverse RFS, however this has not been validated. We reviewed 996 patients with localised RCC who were managed surgically. We provided granularity about the natural history of the NLR after renal surgery, in particular capturing postoperative infections. We did not demonstrate an association between the postoperative NLR and oncological outcomes. Furthermore, we did not demonstrate an association between infections and disease recurrence. This study is the first to explore associations between NLR and the site of disease recurrence. Herein, there was no association between postoperative NLR and metastatic sites. Therefore, our study concludes that NLR monitoring does not have a role in the postoperative setting for patients who have had a localized RCC surgically resected.
Funding
This research was supported by the National Cancer Institute Core Grant (P30 CA008748).
Footnotes
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Declaration of interest
The authors declare no competing interests.
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