UROLOGICAL ONCOLOGY Prognostic Significance of the Neutrophil-to-Lymphocyte Ratio in Patients with Non-Muscle Invasive Bladder Cancer treated with Intravesical Bacillus Calmette–Guérin and the Relationship with the CUETO Scoring Model Jae-Wook Chung1,6†, Jin Woo Kim1†, Eun Hye Lee2, So Young Chun3, Dong Jin Park4, Kyeong Hyeon Byeon1, Seock Hwan Choi5,7, Jun Nyung Lee1,7, Bum Soo Kim5,7, Hyun Tae Kim5,7, Eun Sang Yoo5,7, Tae Gyun Kwon1,6,7, Yun-Sok Ha1,6,7*, Tae-Hwan Kim1,7* Purpose: In this study, we evaluated the predictability of a modified Club Urológico Español de Tratamien- to Oncológico (CUETO) scoring model and preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with non-muscle invasive bladder cancer (NMIBC). Materials and Methods: From August 2005 to May 2016, a total of 281 patients received intravesical bacillus Calmette–Guérin therapy after transurethral resection of a bladder tumor. The pathologic stage of all patients was Ta or T1. Of 281 patients, 84 (29.9%) experienced recurrence and 14 (5.0%) developed progression. The mean follow-up period was 46 months. The cut-off value for NLRs was 2.29. Results: One hundred-eight patients (38.4%) displayed a high NLR (> 2.29). In Kaplan–Meier curve analysis, a high NLR was associated with lower recurrence-free survival (RFS) (P < .001) and progression-free survival (PFS) (P = .002). CUETO scores were associated with RFS (P < .001), but not with PFS (P = .423). A combination of NLRs and the CUETO risk model correlated with RFS (P < .001) and PFS (P = .002). In multivariate analysis, female gender, concomitant carcinoma in situ (CIS), tumor number >3, recurrent tumors, and a high NLR were independent factors predicting recurrence (all P < .05). Concomitant CIS, recurrent tumors, and a high NLR were independent factors for predicting progression (all P < .05). Conclusion: In patients with NMIBC, an NLR >2.29 was identified as a significant factor for predicting tumor recurrence and progression. The inclusion of preoperative NLR enhanced the accuracy of the CUETO model to predict disease progression. Keywords: Neutrophil-to-lymphocyte ratio; Bacillus Calmette–Guérin; Club Urológico Español de Tratamiento Oncológico risk model; Survival INTRODUCTION The most common malignant tumor of the urinary tract is bladder cancer, and the fourth-most com- mon cancer among males in developed countries.(1) Three-quarters of bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC), which includes Tis, Ta and T1 pathologic stages.(2) Transurethral resection of bladder tumor (TUBRT) is a primary surgical treatment used to treat patients with NMIBC.(3) After initial TURBT, immunotherapy with 1 Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea. 2 Joint Institute for Regenerative Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. 3 BioMedical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea. 4 Department of Urology, Dongguk University School of Medicine, Gyeongju, Korea.. 5 Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea. 6 Joint Institute for Regenerative Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. 7 Department of Urology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. † These authors contributed equally to this work. *Correspondence: Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chil- gok Hospital, Daegu, Republic of Korea: Dr. Tae-Hwan Kim, E-mail: doctork@knu.ac.kr, Department of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea. E-mail: yunsokha@gmail.com. Received March 2021 & Accepted September 2021 intravesical instillation of bacillus Calmette–Guérin (BCG) is the most effective adjuvant therapy for inter- mediate- and high-risk NMIBC.(4) Despite the effective- ness and safety of BCG, recurrence rates are 32.6% to 42.1% and progression rates are 9.5% to 13.4%.(5) The major treatment challenge with NMIBC is pre- venting progression to muscle invasive bladder cancer (MIBC), which rapidly worsens prognoses.(6) Thus, it is significant to predict risk factors for disease recurrence and progression in NMIBC patients according to indi- vidual characteristics, including pathology and choose Urology Journal/Vol 19 No. 4/ July-August 2022/ pp. 281-288. [DOI: 10.22037/uj.v18i.6765] optimal treatment modalities to enhance oncologic out- comes. To predict recurrence of NMIBC and progression to MIBC, numerous clinical and pathological factors are commonly used to assign patients to different risk groups. Of these risk models, a scoring model devel- oped by the Club Urológico Español de Tratamiento Oncológico (CUETO, or Spanish Urological Club for Oncological Treatment) is considered the most reliable. The CUETO model was developed as a risk-scoring tool that predicts the probability of disease recurrence and progression in BCG-treated patients at 1, 2, and 5 years.(7) It is now recognized that increased systemic in- flammatory responses induced by tumor microenviron- ments trigger alteration of acute-phase reactive proteins and hematologic parameters.(8) Among these serum markers are neutrophil and lymphocyte counts, which can indicate relative neutrophilia and lymphocytope- nia. In various tumor patients, a higher percentage of neutrophils than lymphocyte is associated with reduced cancer-free and overall survival.(9-11) We evaluated the efficiency of a modified CUETO scoring model combined with preoperative NLRs to predict recurrence and progression of disease in NMIBC patients. PATIENTS AND METHODS Ethics statement This study was approved by the institutional review board of Kyungpook National University, Hospital, Daegu, Republic of Korea (IRB Number KNUH 2020- 03-042). The study was carried out in agreement with the applicable laws and regulations, good clinical prac- tices, and ethical principles as described in the Dec- laration of Helsinki. The institutional review board of Kyungpook National University Chilgok Hospital waived because of the retrospective nature of the study. Study design The study was a single institution, retrospective obser- vational trial. From August 2005 to May 2016, a total of 281 patients who underwent BCG induction thera- py after complete TURBT were included in this study. They had not previously received intravesical BCG and showed no side effects of BCG or signs of recurrence during BCG therapy. All patients were diagnosed as histologically Ta or T1. A second TUR was performed 2 to 4 weeks after initial resection if a bladder tumor specimen did not include detrusor muscle or when a high-grade tumor was detected. Patients with only carcinoma in situ (CIS) were excluded, as were those Significance of the NLR with CUETO model-Chung et al. Total n = 281 NLR ≤ 2.29 n = 173 NLR > 2.29 n = 108 P-value Recurrence 84 (29.9%) 35 (20.2%) 49 (45.4) < 0.001 Progression 14 (5.0%) 3 (1.7%) 11 (10.2%) 0.002 Gender 0.952 Male 245 (87.2%) 151 (87.3%) 94 (87.0%) Female 36 (12.8%) 22 (12.7%) 14 (13.0%) Age, years 67.38 ± 10.58 68.00 ± 9.87 66.40 ± 11.60 0 .218 Age, categorical 0.340 < 60 63 (22.4%) 34 (19.7%) 29 (26.9%) 60 ~ 70 98 (34.9%) 64 (37.0%) 34 (31.5%) > 70 120 (42.7%) 75 (43.4%) 45 (41.7%) Body mass index, kg/m2 23.88 ± 3.37 23.94 ± 3.07 23.79 ± 3.81 0.727 Follow-up periods, months 46.65 ± 20.80 45.25 ± 19.14 48.89 ± 23.13 0.173 T stage 0.239 Ta 105 (37.4%) 60 (34.7%) 45 (41.7%) T1 176 (62.6%) 113 (65.3%) 63 (58.3%) Tumor grade 0.327 Low 30 (10.7%) 16 (9.2%) 14 (13.0%) High 251 (89.3%) 157 (90.8%) 94 (87.0%) Concomitant carcinoma in situ 0.098 No 257 (91.5%) 162 (93.6%) 95 (88.0%) Yes 24 (8.5%) 11 (6.4%) 13 (12.0%) Tumor size 0.779 ≥ 3 cm 195 (69.4%) 119 (68.8%) 76 (70.4%) > 3 cm 86 (30.6%) 54 (31.2%) 32 (29.6%) Tumor number 0.293 ≥3 215 (76.5%) 136 (78.6%) 79 (73.1%) > 3 66 (23.5%) 37 (21.4%) 29 (26.9%) Recurrent tumor 0.792 No 240 (85.4%) 147 (85.0%) 93 (86.1%) yes 41 (14.6%) 26 (15.0%) 15 (13.9%) CUETO score according to recurrence (non-categorical) 5.58 ± 2.13 5.57 ± 2.08 5.59 ± 2.20 0.938 CUETO score according to recurrence (categorical) 0.826 1~4 92 (32.7%) 55 (31.8%) 37 (34.3%) 5~6 106 (37.7%) 67 (38.7%) 39 (36.1%) 7~9 66 (23.5%) 42 (24.3%) 24 (22.2%) 10~16 17 (6.1%) 9 (5.2%) 8 (7.4%) CUETO score according to progression (non-categorical) 8.27 ± 2.26 8.35 ± 2.20 8.15 ± 2.37 0.462 CUETO score according to progression (categorical) 0.453 1~4 22 (7.8%) 12 (6.9%) 10 (9.3%) 5~6 42 (15.0%) 22 (12.7%) 20 (18.5%) 7~9 120 (42.7%) 78 (45.1%) 42 (38.9%) 10~14 97 (34.5%) 61 (35.3%) 36 (33.3%) Table 1. Characteristics of patients with NMIBC. Data are presented as mean ± SD or number (percent) Vol 19 No 4 July-August 2022 282 Urological Oncology 283 found to have advanced bladder or ureteral tumors or non-urothelial carcinoma at the first TUR. Patients with hematologic malignance and acute or chronic infection were also excluded. Preoperative NLR was calculated by a complete blood count with differential. Preoperative NLR was meas- ured once at least 2 weeks before surgery. The best cut- off value of NLR was computed to be 2.29 in accord- ance with the receiver operating characteristic (ROC) curve. And the area under the ROC curve was 0.651 (95% CI 0.578–0.724; P < .001) (sensitivity: 59.5%, specificity: 69.5%) (Figure 1). The follow-up period of patients was calculated from the first TURBT to the last cystoscopy examination. We performed urine cytology, cystoscopy, chest X-ray, and abdominopelvic computed tomography (CT) scans for follow-up study. During the first year after TURBT, follow-up study was conducted at 3, 6, and 12 months. Cystoscopy and urine cytology were performed every 6 months until 2 years after TURBT, and yearly there- after. Imaging analyses, including chest X-ray and CT scans were examined every 6 months from 1 to 5 years, and annually thereafter. Recurrence of disease was defined as a newly patho¬- logical confirmed bladder cancer regardless of stage af- ter completion of BCG induction therapy. Progression of disease was defined as from Ta or T1 to stage T2 or higher disease (MIBC). Intravesical bacillus Calmette–Guérin instillation In all patients, BCG tice strain 12.5 mg (Oncotice) was used. A BCG suspension with 50 mL of 0.9% normal saline was instilled into the bladder via a 10 Fr urethral catheter. Patients were advised not to urinate for two hours. Induction BCG therapy was initiated 2 weeks af- ter TUR and repeated once a week for 6 weeks. We did not perform BCG maintenance therapy. There were no patients who received immediate postoperative instilla- tion of chemotherapy. Club Urológico Español de Tratamiento On- cológico scoring model Scoring tumor recurrence and progression were calcu- lated according to the CUETO scoring model, which includes age, gender, previous recurrence status, tumor stage (2002 TNM classification) and grade, multiplici- ty, and concomitant CIS. In accordance with the 2004 World Health Organization (WHO) grading system, we classified tumor grades as low or high. Statistical analysis Non-continuous variables of patient characteristics, in- cluding gender, T stage, tumor grade, concomitant CIS, size (≤ 3 cm vs > 3 cm), number (≤ 3 vs > 3), recur- rence status and CUETO risk model (categorical) were analyzed using the chi-square test. Student’s t-test was used to analyze continuous variables such as age, body mass index (BMI), CUETO risk model (non-categori- cal) and follow up periods. In addition, univariate and multivariate Cox re¬gression model was used for anal- ysis of tumor recurrence and progression, and Kaplan– Meier curves via a log-rank test were used for analysis of recurrence-free survival (RFS) and progression-free survival (PFS). Statistical analysis was performed us- ing SPSS 16.0 for Windows (SPSS Inc., Chicago, IL, USA), and a P value < .05 was con¬sidered statistically significant. RESULTS Table 1 lists the characteristics of patients with NMIBC. A total of 173 patients had an NRL ≤ 2.29 (61.6%) and 108 (38.4%) had an NLR > 2.29. Eighty-four patients (29.9%) experienced recurrence and 14 (5.0%) showed progression after TUR followed by BCG therapy. Fe- male patients accounted for 12.8% (36/281) of the study groups. No significant differences were evident in gender, age, BMI, and follow-up periods between the two NLR groups. There were no significant differences in tumor T stage, grade, concomitant CIS, size, num- ber, and prior recurrence status between the two NLR groups. No significant differences were found in cate- gorical or non-categorical CUETO scores between the two NLR groups. Table 2 shows subgroup analysis of high risk NMIBC patients (n = 251). High risk group was defined if any high grade tumor or CIS is present. (12) Subgroup analysis of high risk group showed sim- ilar results to the overall group. Table 2. Characteristics of patients with high risk patients with NMIBC. Total n = 251 NRL ≤ 2.29 n = 159 NLR > 2.29 n = 95 P-value Recurrence 78 (30.7%) 34 (21.4%) 44 (46.3%) < 0.001 Progression 14 (5.5%) 3 (1.9%) 11 (11.6%) 0.001 Gender 0.814 Male 223 (87.8%) 139 (87.4%) 84 (88.4%) Female 31 (12.2%) 20 (12.6%) 11 (11.6%) Age, years 67.59 ± 10.61 68.16 ± 9.96 66.64 ± 11.61 0 .270 Body mass index, kg/m2 23.82 ± 3.44 23.91 ± 3.11 23.68 ± 3.94 0.607 Data are presented as mean ± SD or number (percent) No recurrence Recurrence P-value Neutrophil count (x103) 3.97 ± 1.47 4.50 ± 1.44 0.006 Lymphocyte count (x103) 2.03 ± 0.61 1.86 ± 0.69 0.039 NLR 2.11 ± 1.01 2.69 ± 1.17 < 0.001 No progression Progression P-value Neutrophil count (x103) 4.11 ± 1.49 4.59 ± 1.14 0.238 Lymphocyte count (x103) 1.99 ± 0.64 1.65 ± 0.62 0.054 NLR 2.25 ± 1.09 2.98 ± 0.99 0.013 Data are presented as mean±SD or number (percent) Table 3. Absolute neutrophil, lymphocyte count and NLR according to recurrence and progression. Significance of the NLR with CUETO model-Chung et al. Table 3 shows absolute neutrophil, lymphocyte count and NLR according to recurrence and progression. NRL was significantly higher in patients who showed recurrence or progression. Table 4 shows univariate and multivariate Cox propor- tional hazards regression model for predicting recur- rence. Female gender, concomitant CIS, multiplicity (> 3) and an NLR > 2.29 were independent prognostic factors for tumor recurrence (hazard ratio [HR], 2.103; 95% confidence internal [CI], 1.175–3.450; P = .011 / HR, 2.550; 95% CI, 1.362–4.774; P = .033 / HR, 2.275; 95% CI, 1.424–3.635; P = .009 / HR, 2.514; 95% CI, 1.657–3.483; P = .001, respectively). Table 5 shows univariate and multivariate Cox propor- tional hazards regression model for predicting progres- sion. Concomitant CIS, prior recurrence status and an NLR > 2.29 were independent prognostic factors for progression (HR, 10.254; 95% CI, 2.919–36.018; P < .001 / HR, 8.628; 95% CI, 2.446–30.437; P = .041 / HR, 6.119; 95% CI, 1.975–21.622; P = .008, respectively). Kaplan–Meier curve analyses with a log-rank test are shown in Figure 2, 3, and 4. A high NLR (> 2.29) were associated with significantly low RFS and PFS (P < .001, P = .002) (Figure 2). A high CUETO was associ- ated with a significantly low RFS (P < .001), but there was no significant association between CUETO scores and PFS (P = .423) (Figure 3). After combining NLRs (cutoff value = 2.29) and CUETO scoring (cut-off value = 7), the modified risk model showed that high NLR and CUETO scores were significantly associated with low RFS and PFS (P < .001, P = .002) (Figure 4). DISCUSSION This study identified NLR as a significant factor for predicting tumor recurrence and progression, and inclu- sion of preoperative NLR enhanced the accuracy of the CUETO model to predict progression in patients with NMIBC. In the early stages, NMIBC is not life-threatening, but it will recur in more than half of patients and progress from 10% to 20% to MIBC.(13) Although numerous efforts have been made to predict and prevent tumor recurrence and progression, the exact characteristics of NMIBC are unknown due to its heterogeneity. The European Organization for Research and Treat- ment of Cancer (EORTC) has developed a simple scor- ing system that uses information such as tumor size and number, prior recurrence rate, stage, and concomitant CIS and WHO grade based on data of 2596 patients with NMIBC, to predict the risk of relapse and progression. (14) The CUETO scoring model was created to compen- sate for the EORTC with low rates of BCG treatment, using information from 1062 patients who received BCG treatment.(7) Compared to EORTC, where most of the 78% patients received intravesical chemotherapy, all patients in the CUETO study received BCG instilla- tion, and 15% of them received mitomycin C. Intravesical instillation of BCG is a standard treatment for CIS and an adjuvant option for T1 and higher-grade Ta bladder tumors after TUR.(15) The CUETO model is thought to be more suitable for patients treated with BCG. In this study, as with the CUETO study, we in- cluded patients who completed 6 BCG instillations. However, compared with the CUETO scoring model, only female gender, concomitant CIS, multiplicity (> 3), and prior recurrence status were significant factors for predicting tumor recurrence (all P < .05). About tumor progression, only concomitant CIS and prior re- currence status were significant factors (all P < .05). A Kaplan–Meier curve analysis demonstrated that the CUETO score was associated with RFS (P < .05), but not with PFS (P = .423). We, therefore, decided to add the NLR ratio to the CUETO scoring model if inclusion of an NLR would enhance the predictability of CUETO scoring. Preoperative NLR has proven to be a useful marker and a high NLR has been linked to higher tumor stages Table 4. Univariate and multivariate Cox proportional hazards regression model for predicting recurrence. P-value HR (95% CI) Univariate Multivariate Age 0.015 0.271 - Body mass index 0.935 - - Gender (male vs. female) 0.005 0.011 2.103 (1.175-3.450) T stage (Ta vs T1) 0.035 0.236 - Tumor grade (low vs high) 0.475 - - Presence of carcinoma in situ (no vs. yes) 0.024 0.033 2.550 (1.362-4.774) Multiplicity (≤ 3 vs > 3) 0.004 0.009 2.275 (1.424-3.635) Tumor size (≤ 3 vs > 3) 0.715 - - Prior recurrence status (no vs. yes) 0.080 - - NLR (≤ 2.29 vs. > 2.29) < 0.001 0.001 2.514 (1.657-3.483) P-value HR (95% CI) Univariate Multivariate Age 0.089 - - Body mass index 0.722 - - Gender (male vs. female) 0.141 - - T stage (Ta vs T1) 0.225 - - Tumor grade (low vs high) 0.193 - - Presence of carcinoma in situ (no vs. yes) < 0.001 < 0.001 10.254 (2.919-36.018) Multiplicity (≤ 3 vs > 3) 0.645 - - Tumor size (≤ 3 vs > 3) 0.670 - - Prior recurrence status (no vs. yes) 0.022 0.041 8.628 (2.446-30.437) NLR (≤ 2.29 vs. > 2.29) 0.002 0.008 6.119 (1.975-21.622) Table 5. Univariate and multivariate Cox proportional hazards regression model for predicting progression. Significance of the NLR with CUETO model-Chung et al. Vol 19 No 4 July-August 2022 284 Urological Oncology 212 and adverse oncologic outcomes in numerous cancers, including not only the gastrointestinal cancer but gen- itourinary tract cancer, such as urothelial carcinoma of the bladder.(16-19) Although the pathophysiology is not understood clearly, relative neutrophilia may increase inflammatory markers that include proangiogenic fac- tors, growth factors, proteases, and antiapoptotic mark- ers, which facilitate tumor growth and progression.(20) In addition, lymphocytopenia may destroy cell-mediated immune responses and therefore worsen prognoses.(21) In bladder tumors, several previous studies have evalu- ated the predictive value of NLRs(22); most focused on MIBC and were conducted mainly on patients who un- derwent radical cystectomy.(23-26) In 2014, Viers et al. evaluated 899 patients who underwent radical cystec- tomy without neo-adjuvant chemotherapy and who had a preoperative NLR. An elevated preoperative NLR (> 2.7) was associated with a significantly higher risk of a locally advanced disease as well as subsequent dis- ease recurrence and cancer-specific and all-cause mor- tality. In 2012, Can et al. demonstrated that among 80 NMIBC patients and 102 patients with MIBC, an NLR > 2.57 was a predictor of invasive urothelial carcinoma. According to a 2014 study by Potretzke et al., among 102 consecutive patients undergoing radical cystecto- my, NLR was significantly related to pathologic tumor staging and to upstaging of non-organ confined disease (≥ pT3). Similarly, Krane et al. reported that, among Figure 1. The best cut-off NLR value according to the ROC curve. Figure 2. Kaplan–Meier curve analysis for recurrence-free survival (A) and progression-free survival (B), according to NLRs. Significance of the NLR with CUETO model-Chung et al. Urological Oncology 285 68 consecutive cases of radical cystectomy for MIBC, an NLR >2.5 was associated with poor overall and can- cer-specific survival, suggesting that such patients may benefit from neo-adjuvant chemotherapy. When focusing on NMIBC, several trials(8,16,27,28) eval- uated the predictive value of the NLR. In 2015, Mano et al. revealed that an NLR > 2.41 was an independent predictor of disease progression and recurrence in 107 patients with NMIBC treated with TUR. According to Favilla et al.’s study in 2016, an NLR ≥ 3 was associ- ated with worse disease recurrence (HR, 2.84; P < .01) in 178 patients with Ta or T1 bladder tumor who un- derwent TUR. The 5-year RFS was 49% and 62% in patients with an NLR ≥ 3 and < 3 (P < .01). A prospec- tive study of Albayrak et al. in 2016 found that a higher NLR was associated with recurrence and progression of Ta or Ta bladder tumors, although, and in contrast with the finding of previous studies, a significant rela- tionship with NLR was lost after correcting for age. An- other prospective trial by Getzler et al. in 2018 demon- strated that an NLR > 2.5 was a significant predictor of disease recurrence and a worse RFS in 113 patients with NMIBC, particularly those treated with BCG. As with the studies described above, we found that an NLR > 2.29 was associated with higher tumor recurrence (HR, 2.451; 95% CI, 1.567–3.834; P < .001) and tu- mor progression (HR, 5.911; 95% CI, 1.579–22.126; P = .008) according to a multivariate Cox proportional hazards regression model. Kaplan–Meier curve analy- sis showed that an NLR > 2.29 showed significantly low RFS and PFS (P < .001 and < .002, respectively). However, the four studies mentioned above were not restricted to patients treated with BCG. When narrowing the scope of predictive values of NLRs in all BCG treated patients, Racioppi et al. (2019)(29) evaluated whether an NLR ratio can predict the response to BCG in high-risk NMIBC patients. One hundred consecutive patients with newly diagnosed Figure 3. Kaplan–Meier curve analysis for recurrence-free survival (A) and progression-free survival (B), according to CUETO scores. Figure 4. Kaplan–Meier curve analysis for recurrence-free survival (A) and progression-free survival (B), according to a combination of NLRs and CUETO scores. Significance of the NLR with CUETO model-Chung et al. Vol 19 No 4 July-August 2022 286 high-risk NMIBC were analyzed retrospectively. All received an induction course of intravesical immu¬no- therapy with BCG followed by a maintenance course for at least a year. Forty-eight patients underwent radi- cal cystectomy for high-grade recurrence or pro¬gres- sion to muscle invasive disease (BCG non-responder group). The mean NLR was 2.61 ± 0.77 in the BCG responder group and 3.65 ± 1.16 in the BCG non-re- sponder group (P = .01). The NLR was associated with both recurrence (P = .01) and progression (P = .01). A Kaplan–Meier analysis with a log-rank test showed statistically significant differences between the curves for an NLR < 3 and an NLR ≥ 3 (P < .05). Based on the ability of the NLR to predict tumor recur- rence and progression, we added the NLR to the CUE- TO scoring model. Using the CUETO scoring model alone, a significant association was observed with low RFS (P < .001), but not with PFS (P = .423) (Figure 2). However, after combining the NLR (cut-off value 2.29) and CUETO scoring model (cut-off value 7), the result- ing modified risk model showed that a high NLR and high CUETO score were significantly associated with both low RFS and PFS (P < .001 and P = .002, respec- tively) (Figure 3). Other combined risk models have been shown to enhance the predictability of each risk model.(8,21) Getzler et al. provided statistical evidence that an NLR > 2.5 may improve the predictive power of an EORTC score when the two are calculated together. In 2019, Aydin et al. evaluated the correlation between NLR and EORTC recurrence and progression scores. They reported that as the NLR increased, recurrence (P < .001) and progression (P = .034) scores increased significantly. Nevertheless, this study is the first to analyze the prognostic significance of the NLR and its synergic relation with the CUETO scoring model in pa- tients with NMIBC after intravesical BCG instillation. Furthermore, interestingly, there were no differences in the clinical and pathological findings between the two NLR groups. And this highlights that the biological properties of tumor cells may be very different from the pathological and anatomical characteristics of the tumor. As such patients within a specific pathological classification may have differing prognosis due to dif- fering biological properties such as the degree of im- mune dysfunction. There were several limitations to be considered in this study. First, it was based on a retrospective analysis of the records of patients treated at a single institution with unavoidable selection biases. Small numbers and heter- ogeneous patients are also weak points. It should also be noted that in many previous studies, various NLR cut-off values were evaluated and utilized.(30) Each study’s results should be interpreted carefully. Because the idealized and generalized NLR have not yet been established, each study selected cut-off values with dif- ferent sensitivities and specificities. Furthermore, the main limitation concerning NLRs is the volatile counts of neutrophils and lymphocytes. Although we exclud- ed patients with hematologic malignances and acute or chronic infections, it is possible that individual chronic medications, herbs, or antibiotics affected the NLR val- ue. As the NLR is a dynamic parameter (unlike stand- ard pathological parameters), the dynamic changes of NLR after various treatments of bladder cancer may be important in the clinical day-to-day management of patients. Few studies have been reported on the NLR measured after TURBT or BCG instillation, therefore, studies comparing NLR before and after treatment of bladder cancer or optimal timing of NLR determination are also essential, either. A prospective study with a larger cohort is required to solidify the place of NLR in predicting disease recurrence and progression in pa- tients with NMIBC in the future. CONCLUSIONS Our study showed that in patients with NMIBC, the NLR was identified as a significant factor for predicting tumor recurrence and progression. Furthermore, inclu- sion of a preoperative NLR enhanced the accuracy of the CUETO model to predict disease progression. NLR is promising and inexpensive hematologic biomarker which can be applied to clinical decision making and estimation of oncologic outcomes in the bladder cancer patients. We therefore recommend that patients with a high NLR receive more aggressive management. ACKNOWLEDGEMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), and was funded by the Korean Government (MSIT) (2016R1C1B1011180), (2019R1H1A1079839), (2019R1F1A1044473), (2019R1A2C1004046), (2018R1C1B5040264), (2020R1A2B5B03002344) and (2020R1I1A3071568). CONFLICT OF INTERESTS None of the authors has any personal or financial con¬- flict of interest. REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-86. 2. Babjuk M, Burger M, Zigeuner R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013;64:639-53. 3. Babjuk M, Bohle A, Burger M, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71:447-61. 4. Malmstrom PU, Sylvester RJ, Crawford DE, et al. 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