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Systemic Immune-inflammation Index (SII) during Induction has Higher Predictive Value Than Preoperative SII in Non-muscle-invasive Bladder Cancer Patients Receiving Intravesical Bacillus Calmette -Guerin

  • Author Footnotes
    # Both authors contributed equally to this work and were listed as co-first authors.
    Li Deng-xiong
    Footnotes
    # Both authors contributed equally to this work and were listed as co-first authors.
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Author Footnotes
    # Both authors contributed equally to this work and were listed as co-first authors.
    Yu Qing-xin
    Footnotes
    # Both authors contributed equally to this work and were listed as co-first authors.
    Affiliations
    Department of Pathology, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang Province, 317000, China
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  • Feng De-chao
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Zhang Fa-cai
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Wu Rui-cheng
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Xu Shi
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Ping Han
    Correspondence
    Corresponding author. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Guoxue Xiang #37, Chengdu, Sichuan Province, 610041, China
    Affiliations
    Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
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  • Author Footnotes
    # Both authors contributed equally to this work and were listed as co-first authors.
Open AccessPublished:November 19, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.013

      Clinical Practice Points

      • Urologists are continually devoted to finding a powerful prognostic factor to screen out patients who have no response to BCG and should accept early aggressive treatment. The prognostic value of the ISII remains unclear in NMIBC patients receiving BCG, which might be a power predictor.
      • This study respectively collected data from 362 NMIBC patients receiving BCG treatment in our institution to determine and compare the prognostic value of the ISII, PSII and PISII.
      • This study first found that ISII could independently predict the prognosis of NMIBC patients receiving BCG.
      • ISII was associated with higher prognostic value than PSII and PISII, which might help to select an optimal treatment schedule for patients with NMIBC.

      Abstract

      Background

      The prognostic value of the systemic immune-inflammation index during induction (ISII) remains unclear in non-muscle-invasive bladder cancer (NMIBC) patients receiving Bacillus Calmette-Guérin (BCG). We aimed to determine and compare the prognostic value of the ISII, preoperative systemic immune-inflammation index (PSII) and their dynamic changes (PISII).

      Methods

      This study respectively collected data from 362 NMIBC patients receiving BCG treatment in our institution. The prognostic values of PSII, ISII and PISII were analyzed by the Kaplan−Meier method and Cox proportional hazard regression models. The concordance index and receiver operating characteristic curve analysis were employed to compare the prognostic value of these three factors.

      Results

      Our study enrolled 197 patients. These patients included 170 male patients, and the mean age was 64.17 years. During the follow-up time, 85 patients experienced recurrence and 55 patients found progression. According to the results of Cox multivariable analysis, PSII (P=0.001) and ISII (P<0.001) could independently predict the recurrence of NMIBC patients receiving BCG. Meanwhile, PSII (P=0.025) and ISII (P<0.001) were also independent prognostic factors of progression. Compared with PSII, ISII was associated with better accuracy for NMIBC patients receiving BCG.

      Conclusions

      This study first found that ISII could independently predict the prognosis of NMIBC patients receiving BCG. Furthermore, we also identified that ISII was associated with higher prognostic value than PSII and PISII, which might help to select an optimal treatment schedule for patients with NMIBC.

      Micro-abstract

      The prognostic value of the systemic immune-inflammation index during induction (ISII) remains unclear in non-muscle-invasive bladder cancer (NMIBC) patients receiving Bacillus Calmette-Guérin (BCG). This study first found that ISII could independently predict the prognosis of NMIBC patients receiving BCG, which might help to select an optimal treatment schedule for patients with NMIBC.

      Keywords

      Abbreviations:

      PSII (Preoperative systemic immune-inflammation index), ISII (Systemic immune-inflammation index during induction), PISII (Preoperative dividing by induction systemic immune-inflammation index), TURBT (Transurethral resection of bladder tumor), NMIBC (Non-muscle-invasive bladder cancer), BCG (Bacillus Calmette-Guérin), HV (Histological variant), WHO (World Health Organization), SD (Standard Deviation), HR (Hazard ratio), BMI (Body mass index), CI (Confidence level), RFS (Recurrence-free survival), PFS (Progression-free survival)

      Introduction

      Bladder cancer is the 10th most commonly diagnosed carcinoma worldwide and caused 213,000 deaths in 2020
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      . Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancers and easily recurs and progress after transurethral resection of bladder tumor (TURBT). Fortunately, since Bacillus Calmette-Guérin (BCG) was used clinically, the rates of recurrence and progression have obviously declined in recent decades. Nevertheless, almost 30% of NMIBC patients do not respond to BCG treatment
      EAU Guidelines
      . For patients with BCG failure or high-risk patients, various aggressive therapies are employed to improve their prognosis. For instance, some urologists suggested that patients with BCG failure or high-risk patients might accept early radical cystectomy rather than intravesical therapies
      EAU Guidelines
      • Chang SS
      • Boorjian SA
      • Chou R
      • et al.
      Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline.
      • Shi X
      • Feng D
      • Wei W
      A Systematic Review and Meta-Analysis Protocol of Chemoablation vs. Transurethral Resection of Bladder Tumor in Patients With Non-Muscle-Invasive Bladder Cancer.
      . However, radical cystectomy has considerable morbidity, even in high-volume centers of excellence and regardless of open versus robotic approaches
      • Chang SS
      • Boorjian SA
      • Chou R
      • et al.
      Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline.
      ,
      • Feng D
      • Li A
      • Hu X
      • et al.
      Comparative effectiveness of open, laparoscopic and robot-assisted radical cystectomy for bladder cancer: a systematic review and network meta-analysis.
      ,
      • Feng D
      • Wang Z
      • Yang Y
      • et al.
      Incidence and risk factors of parastomal hernia after radical cystectomy and ileal conduit diversion: a systematic review and meta-analysis.
      . Given this condition, urologists must weigh carefully to determine whether aggressive treatments should be performed. Thus, urologists are continually devoted to finding a powerful prognostic factor to screen out patients who have no response to BCG and should accept early aggressive treatment.
      It is widely reported that the preoperative systemic immune-inflammation index (PSII) can independently predict the prognosis of many malignant tumors, such as lung, hepatocellular, kidney and prostate cancers
      • Zhong JH
      • Huang DH
      • Chen ZY.
      Prognostic role of systemic immune-inflammation index in solid tumors: a systematic review and meta-analysis.
      . Recent evidence suggests that PSII can be an independent prognostic factor for NMIBC patients receiving BCG and is associated with pathological features
      • Bi H
      • Shang Z
      • Jia C
      • et al.
      Predictive Values of Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Long-Term Survival in High-Risk Non-Muscle-Invasive Bladder Cancer Patients: A Single-Centre Retrospective Study.
      • Akan S
      • Ediz C
      • Sahin A
      • et al.
      Can the systemic immune inflammation index be a predictor of BCG response in patients with high-risk non-muscle invasive bladder cancer?.
      • Ke ZB
      • Chen H
      • Chen JY
      • et al.
      Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer.
      . Trained immunity is an important mechanism mediating BCG immunotherapy
      • van Puffelen JH
      • Keating ST
      • Oosterwijk E
      • et al.
      Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer.
      . Cytokines, including IL-1β, TNF, IL-10 and GM-CSF, are significantly increased after the first BCG instillation
      • Bisiaux A
      • Thiounn N
      • Timsit MO
      • et al.
      Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer.
      ,
      • Calais S
      • Paula V
      • Dário L
      • et al.
      Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more.
      and can also predict the recurrence of patients receiving BCG
      • Kamat AM
      • Briggman J
      • Urbauer DL
      • et al.
      Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin.
      . Neutrophils and lymphocytes are the main components of trained immunity and are significantly increased after the first BCG instillation
      • Bisiaux A
      • Thiounn N
      • Timsit MO
      • et al.
      Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer.
      . Thus, we reasonably assumed that the systemic immune-inflammation index during induction (ISII) might be a powerful prognostic factor for NMIBC patients receiving BCG. However, no study has reported the prognostic value of ISII in patients who received BCG.
      To clarify the prognostic value of the ISII, we collected data from NMIBC patients receiving BCG treatment in our institution after approval by ethics committee. The first purpose was to identify the prognostic value of PSII, ISII and their dynamic change (PISII). The second purpose was to compare the prognostic value of these three factors.

      Materials and Methods

      Patient selection and data collection

      We collected the data of NMIBC patients receiving BCG in our hospital from 2014 to 2020 after approval by our institutional ethics committee (approval number: 20201045). Patients included in our study should have blood cell data before surgery and during BCG induction. PSII or ISII=neutrophil count (109/L) *platelet count (109/L)/lymphocyte count (109/L). In detail, PSII should be determined two weeks before surgery, while ISII was generated by blood counts measured during BCG induction. PISII=PSII/ISII. The exclusion criteria for selecting the patients were as follows: patients with diseases that could affect the results of blood counts (such as prostatitis, cystitis, urinary tract infection, yeast infections, endometriosis and systemic inflammatory disease), those with missing data, other sites of carcinoma, and those who received other intravesical chemotherapy (except immediate single instillation after TURBT).
      Experienced pathologists carefully evaluated all specimens included in this study. Pathological information, including tumor stage, World Health Organization (WHO) grade and carcinoma in situ (CIS), was reviewed referring to the 2016 WHO bladder cancer classification
      • Humphrey PA
      • Moch H
      • Cubilla AL
      • et al.
      The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours.
      and the 2016 American Joint Committee on Cancer

      Amin MB, E.S., Greene FL, Byrd DR, et al. AJCC cancer staging manual. 8th ed.

      . Of these, NMIBC would be considered as histological variant (HV) NMIBC if any HV appeared in the specimens. Moreover, demographic and clinical outcomes were also determined in this study.

      Patient management and follow-up

      All patients in this study received intravesical BCG therapy. Specifically, induction BCG instillations were performed once a week for 6 weeks. After BCG induction, at least one year of maintenance instillations would be given every fortnight if the patient's condition permits
      EAU Guidelines
      . Patients accepted cystoscopy and urinary cytology every 3 months for the first year, every 6 months 2 to 5 years after TURBT, and then annually. Moreover, imaging and laboratory examination were performed if patients were in need. Recurrence-free survival (RFS) was defined the time from the date of surgery to local or distant recurrence. Progression-free survival (PFS) was defined as an increase in the stage to MIBC and/or metastasis.

      Statistical analysis

      Categorical and continuous variables between groups were analyzed using Chi-square and Student's t-tests, respectively. Fisher's exact test was applied to estimate categorical variables when one or more of the cell counts in a 2 × 2 table were less than 5. The best cut-off values of PSII and ISII were generated by the receiver operating characteristic curve (ROC) and Youden index. The prognosis, including RFS and PFS, was validated by the Kaplan−Meier method, and comparisons between groups were performed by log-rank tests. Univariable and multivariable Cox proportional hazard regression models were employed to evaluate the association of PSII, ISII and PISII with RFS and PFS. For comparison of the prognostic value of PSII, ISII and PISII, the concordance index (C-index) and multiparameter ROC analysis were used to validate the accuracy of different multivariable Cox proportional hazard regression models. A P<0.05 was considered significant for all analyses, which were performed using R version 3.6.3 and relative packages.

      Results

      Demographic and clinicopathologic characteristics

      Our study finally selected 197 patients from 362 NMIBC patients receiving BCG. The mean ± standard deviation (SD) follow-up time was 30.18±15.67 months. For PSII and ISII, the optimal cut-off values were 557 and 517, respectively. Then, referring to the cut-off value, all patients were divided into high and low groups. In PISII, patients with PISII>1 were regarded as the high PISII group, and the others were regarded as low PISII group. A total of 21/197 (10.6%) patients exhibited side effects, with cystitis being the most common. To compare the difference between the high and low groups, Table 1 showed that patients in the high ISII group were associated with a large tumor size, and there were more patients with hypertension than in the low ISII group. Patients in the high PISII group were positively correlated with tumor number. The remaining detailed information was provided in Table 1.
      Table 1Demographic and clinicopathologic characteristics.
      TotalPSIIISIIPISII
      197Low (160)High (37)P valueLow (119)High (78)P valueLow (75)High (122)P value
      Sex0.8200.9360.448
      Female27(13.7%)21 (10.7%)6 (3%)17 (8.6%)10 (5.1%)8 (4.1%)19 (9.6%)
      Male170(86.3%)139 (70.6%)31 (15.7%)102 (51.8%)68 (34.5%)67 (34%)103 (52.3%)
      Age64.1764.5362.590.33963.8964.590.66664.7763.80.549
      ±11.05± 11.0± 11.45± 11.2± 10.95± 11.68± 10.73
      BMI23.6523.822.980.14223.9723.150.06323.6923.620.864
      ±3.04± 2.93± 3.47± 2.84± 3.3± 3.28± 2.91
      Smoker0.6280.5060.476
      No140(71.1%)112 (56.9%)28 (14.2%)82 (41.6%)58 (29.4%)56 (28.4%)84 (42.6%)
      Yes57(28.9%)48 (24.4%)9 (4.6%)37 (18.8%)20 (10.2%)19 (9.6%)38 (19.3%)
      Gross hematuria0.6230.5550.725
      No46(23.4%)39 (19.8%)7 (3.6%)30 (15.2%)16 (8.1%)16 (8.1%)30 (15.2%)
      Yes151(76.6%)121 (61.4%)30 (15.2%)89 (45.2%)62 (31.5%)59 (29.9%)92 (46.7%)
      Hypertension0.4700.0110.796
      No140(71.1%)116 (58.9%)24 (12.2%)93 (47.2%)47 (23.9%)52 (26.4%)88 (44.7%)
      Yes57(28.9%)44 (22.3%)13 (6.6%)26 (13.2%)31 (15.7%)23 (11.7%)34 (17.3%)
      Diabetes0.1770.2940.654
      No172(87.3%)137 (69.5%)35 (17.8%)101 (51.3%)71 (36%)67 (34%)105 (53.3%)
      Yes25(12.7%)23 (11.7%)2 (1%)18 (9.1%)7 (3.6%)8 (4.1%)17 (8.6%)
      Tumor size
      : For multiple tumors, the diameter of the largest tumor was regarded as tumor size. BMI: Body mass index; WHO: World Health Organization; CIS: Carcinoma in situ; HV: Histological variant; PSII: Preoperative systemic immune-inflammation index; ISII: Systemic immune-inflammation index during induction; PISII: Preoperative dividing by induction systemic immune-inflammation index.
      0.6700.0080.285
      <=3cm110(55.8%)91 (46.2%)19 (9.6%)76 (38.6%)34 (17.3%)46 (23.4%)64 (32.5%)
      >3cm87(44.2%)69 (35%)18 (9.1%)43 (21.8%)44 (22.3%)29 (14.7%)58 (29.4%)
      Tumor number0.1790.2970.046
      Single86(43.7%)74 (37.6%)12 (6.1%)56 (28.4%)30 (15.2%)40 (20.3%)46 (23.4%)
      Multiple111(56.3%)86 (43.7%)25 (12.7%)63 (32%)48 (24.4%)35 (17.8%)76 (38.6%)
      WHO grade0.7360.6780.136
      Low55(27.9%)46 (23.4%)9 (4.6%)35 (17.8%)20 (10.2%)26 (13.2%)29 (14.7%)
      High142(72.1%)114 (57.9%)28 (14.2%)84 (42.6%)58 (29.4%)49 (24.9%)93 (47.2%)
      CIS0.3120.4290.221
      No182(92.4%)146 (74.1%)36 (18.3%)108 (54.8%)74 (37.6%)72 (36.5%)110 (55.8%)
      Yes15(7.6%)14 (7.1%)1 (0.5%)11 (5.6%)4 (2%)3 (1.5%)12 (6.1%)
      T stage0.6541.0000.407
      Ta40(20.3%)31 (15.7%)9 (4.6%)24 (12.2%)16 (8.1%)18 (9.1%)22 (11.2%)
      T1157(79.7%)129 (65.5%)28 (14.2%)95 (48.2%)62 (31.5%)57 (28.9%)100 (50.8%)
      Histology0.5910.9290.118
      No HV171(86.8%)140 (71.1%)31 (15.7%)104 (52.8%)67 (34%)61 (31%)110 (55.8%)
      HV26(13.2%)20 (10.2%)6 (3%)15 (7.6%)11 (5.6%)14 (7.1%)12 (6.1%)
      Recurrence0.006< 0.0010.397
      No112(56.9%)99 (50.3%)13 (6.6%)80 (40.6%)32 (16.2%)46 (23.4%)66 (33.5%)
      Yes85(43.1%)61 (31%)24 (12.2%)39 (19.8%)46 (23.4%)29 (14.7%)56 (28.4%)
      Progression0.012< 0.0010.261
      No142(72.1%)122 (61.9%)20 (10.2%)98 (49.7%)44 (22.3%)58 (29.4%)84 (42.6%)
      Yes55(27.9%)38 (19.3%)17 (8.6%)21 (10.7%)34 (17.3%)17 (8.6%)38 (19.3%)
      a : For multiple tumors, the diameter of the largest tumor was regarded as tumor size. BMI: Body mass index; WHO: World Health Organization; CIS: Carcinoma in situ; HV: Histological variant; PSII: Preoperative systemic immune-inflammation index; ISII: Systemic immune-inflammation index during induction; PISII: Preoperative dividing by induction systemic immune-inflammation index.

      The relationship between RFS and PSII, ISII and PISII

      There were 85/197 (43.1%) patients who were diagnosed with recurrence during follow-up. The results of the Chi-square analysis showed that patients with high PSII were associated with a significantly higher recurrence rate (Table 1, P=0.006). The correlation between RFS and PSII was also identified by the results of log-rank tests (Figure 1A, P=0.004) and univariable analysis (Figure 2A, P=0.001). Moreover, multivariable analysis demonstrated that PSII was an independent prognostic factor of NMIBC patients receiving BCG (Figure 2B, P=0.005).
      Figure 1
      Figure 1Kaplan-Meier estimates for recurrence and progression
      Figure 2
      Figure 2Univariate and multivariate Cox Proportional Hazard model for recurrence: A: univariate results, B: multivariate results with PSII, C: multivariate results with ISII, D: multivariate results with PISII. PSII: Preoperative systemic immune-inflammation index; ISII: Systemic immune-inflammation index during induction; PISII: Preoperative dividing by induction systemic immune-inflammation index; *: P<0.05; **:P<0.01; ***:P<0.001;
      For ISII, patients with high ISII were positively related to the recurrence rate according to the results of Chi-square analysis (Table 1, P<0.001). Similarly, the relationship between RFS and ISII was identified by the results of log-rank tests (Figure 1B, P<0.001) and univariable analysis (Figure 2A, P<0.001). Further multivariable analysis illustrated that ISII was an independent prognostic factor of NMIBC patients receiving BCG (Figure 2C, P<0.001). There was no significant difference in RFS between the high and low PISII groups according to the results of the Chi-square analysis (Table 1, P=0.448), log-rank tests (Figure 1C, P=0.308), univariable analysis (Figure 2A, P=0.309) and multivariable analyses (Figure 2D, P=0.854).

      The relationship between PFS and PSII, ISII and PISII

      The total number of progressions was 55/197 (27.9%) at the end of follow-up. Based on Chi-square analysis, patients with high PSII were positively associated with the recurrence rate (Table 1, P=0.012). It was easier for patients in the high PSII group to progress according to log-rank tests (Figure 1D, P=0.006) and univariable analysis (Figure 3A, P=0.007). Further multivariable analysis indicated that PSII could independently predict the prognosis of NMIBC patients receiving BCG (Figure 3B, P=0.025).
      Figure 3
      Figure 3Univariate and multivariate Cox Proportional Hazard model for progression: A: univariate results, B: multivariate results with PSII, C: multivariate results with ISII, D: multivariate results with PISII. PSII: Preoperative systemic immune-inflammation index; ISII: Systemic immune-inflammation index during induction; PISII: Preoperative dividing by induction systemic immune-inflammation index; *: P<0.05; **:P<0.01; ***:P<0.001;
      Compared with the low ISII group, the high ISII was positively associated with the progression rate according to the Chi-square analysis (Table 1, P<0.001), log-rank tests (Figure 1E, P<0.001) and univariable analysis (Figure 3A, P<0.001). Furthermore, ISII was an independent prognostic factor for NMIBC patients receiving BCG (Figure 3C, P<0.001). PISII could not be a predicter for progression according to Chi-square analysis (Table 1, P=0.408), log-rank tests (Figure 1F, P=0.089), univariable analysis (Figure 3A, P=0.093) and multivariable analysis (Figure 3D, P=0.537).

      Validation of the accuracy and reliability of PSII and ISII

      For recurrence, the area under curve (AUC) value of ISII was 0.624, 0.701, and 0.759 in 1, 2, 3 years, respectively (Figure 4A). The AUC value of PSII was lower than that of ISII, which was 0.622, 0.661, and 0.667 in 1, 2, 3 years, respectively (Figure 4B). Meanwhile, the model including ISII (C-index=0.665, 95% confidence interval (CI)=0.632-0.698) had higher accuracy than PSII (C-index=0.633, 95%CI=0.601-0.664). For progression, the AUC value of ISII (Figure 4C) was higher than that of PSII (Figure 4D). Similarly, ISII showed higher accuracy (C-index=0.737, 95%CI=0.700-0.775) than PSII (C-index=0.685, 95%CI=0.647-0.722).
      Figure 4
      Figure 4The ROC plots of ISII (A), PSII (B) in recurrence. The ROC plots of ISII (C), PSII (D) in progression. PSII: Preoperative systemic immune-inflammation index; ISII: Systemic immune-inflammation index during induction;

      Discussion

      The prognostic value of PSII has widely attracted the attention of doctors. Therefore, urologists also intend to clarify the role of PSII in BCG treatment to screen out NMIBC patients who may fail to response to BCG. In the current study, we not only identified that PSII had independent prognostic ability but also illustrated for the first time that ISII could independently predict the prognosis of NMIBC patients receiving BCG. Furthermore, compared with the PSII and PISII, the ISII was a better prognostic factor for NMIBC patients receiving BCG.
      Tumor-related inflammation has been widely studied and listed as a major phenotype of malignant tumors
      • Hanahan D.
      Hallmarks of Cancer: New Dimensions.
      . Meanwhile, inflammatory and immune cells are important parts of the tumor microenvironment and indispensable factors in promoting tumor proliferation, tumor progression, survival and migration
      • Okada F
      • Izutsu R
      • Goto K
      • et al.
      Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects.
      . Bladder cancer is an inflammation- and immune-related malignant tumor. The inflammatory and immune environments of peripheral blood and tumors are significantly changed during BCG induction
      • van Puffelen JH
      • Keating ST
      • Oosterwijk E
      • et al.
      Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer.
      . Therefore, it is important for urologists to clarify the role of peripheral immune cells in NMIBC.
      Similar to prostate-specific antigen, a widely recognized cut-off value can significantly promote the clinical application of SII and help doctors select the optimal treatment plan. The optimal cut-off values of PSII and ISII were 557 and 517 in our study, respectively, which were consistent with most studies. Similarly, Ke et al.
      • Ke ZB
      • Chen H
      • Chen JY
      • et al.
      Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer.
      obtained that the optimal cut-off value of PSII was 439.8 by analyzing NMIBC patients receiving BCG. This value was in agreement with Bi et al.’s
      • Akan S
      • Ediz C
      • Sahin A
      • et al.
      Can the systemic immune inflammation index be a predictor of BCG response in patients with high-risk non-muscle invasive bladder cancer?.
      finding, which suggested that 467.76 was the best cut-off value of PSII by analyzing NMIBC patients receiving BCG. Akan et al.
      • Bi H
      • Shang Z
      • Jia C
      • et al.
      Predictive Values of Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Long-Term Survival in High-Risk Non-Muscle-Invasive Bladder Cancer Patients: A Single-Centre Retrospective Study.
      believed that 672 and 624 were the best PSII cut-off values for the recurrence and progression of NMIBC patients receiving BCG, respectively. Moreover, Katayama et al.
      • Katayama S
      • Mori K
      • Pradere B
      • et al.
      Prognostic value of the systemic immune-inflammation index in non-muscle invasive bladder cancer.
      calculated that the cut-off value of PSII was 580, which enrolled 1117 patients with NMIBC. A study reported that 276.6 was the best cut-off value of PSII in 216 NMIBC patients receiving various chemotherapies
      • Zhao R
      • Shan J
      • Nie L
      • et al.
      The predictive value of the ratio of the product of neutrophils and hemoglobin to lymphocytes in non-muscular invasive bladder cancer patients with postoperative recurrence.
      . These results suggested that the optimal cut-off value was different among studies. Despite differences, most cut-off values of PSII are usually approximately 500 in patients with NMIBC. This phenomenon was beneficial to the clinical practice of PSII and ISII.
      The prognostic value of PSII was first reported in patients undergoing radical cystectomy rather than NMIBC
      • Zhang W
      • Wang R
      • Ma W
      • et al.
      Systemic immune-inflammation index predicts prognosis of bladder cancer patients after radical cystectomy.
      . Subsequent studies also demonstrated the prognostic value of PSII in muscle invasive bladder cancer
      • Grossmann NC
      • Schuettfort VM
      • Pradere B
      • et al.
      Impact of preoperative systemic immune-inflammation Index on oncologic outcomes in bladder cancer patients treated with radical cystectomy.
      . An initial objective of the study was to clarify the prognostic value of PSII, ISII and PISII in NMIBC patients receiving BCG. Recently, several studies have reported that PSII could predict the prognosis of patients with NMIBC. For instance, Ke et al
      • Ke ZB
      • Chen H
      • Chen JY
      • et al.
      Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer.
      illustrated that high PSII was associated with worse RFS according to the results of log-rank tests. This finding was consistent with Zhao et al.
      • Wang QH
      • Ji JL
      • Li H
      • et al.
      Preoperative Lymphocyte-to-monocyte Ratio Predicts Prognosis in Patients with Stage T1 Non-muscle Invasive Bladder Cancer.
      , who demonstrated that PSII could independently predict the RFS of NMIBC patients receiving various treatments. Similarly, PSII could also independently predict the PFS in patients with NMIBC receiving various chemotherapies by multivariable analysis
      • Katayama S
      • Mori K
      • Pradere B
      • et al.
      Prognostic value of the systemic immune-inflammation index in non-muscle invasive bladder cancer.
      . This finding was also reported by Akan et al
      • Akan S
      • Ediz C
      • Sahin A
      • et al.
      Can the systemic immune inflammation index be a predictor of BCG response in patients with high-risk non-muscle invasive bladder cancer?.
      .
      Furthermore, high PSII was associated with worse cancer-free survival and overall survival
      • Bi H
      • Shang Z
      • Jia C
      • et al.
      Predictive Values of Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Long-Term Survival in High-Risk Non-Muscle-Invasive Bladder Cancer Patients: A Single-Centre Retrospective Study.
      . Consistent with these studies, our study found that patients with high PSII were associated with worse RFS and PFS, again identifying the independent prognostic value of PSII. No study reported the prognostic value of ISII and PISII. In this study, the PISII failed to be an independent prognostic factor for RFS and PFS. In the current study, we first identified that ISII could predict the prognosis of NMIBC patients receiving BCG. Further analysis demonstrated that the model containing the ISII had higher accuracy than the model including the PISII. ISII was generated by blood tests measured during BCG induction so that NMIBC patients could predict the outcome of BCG immunotherapy early and adjust the treatment plan in time. These results supported that the ISII might help urologists to select an optimal treatment schedule for patients with NMIBC.
      A few limitations should be mentioned, including those inherent to the retrospective design of the study. The bias of data might be noticed because the data were derived from a hospital information system. Therefore, we used strict exclusion criteria to avoid possible bias. Additionally, though the number of enrolled patients permits us to perform multivariable analysis, prospective and large-scale studies are still required for more representative samples with higher statistical power.

      Conclusion

      This study first found that the ISII could independently predict the prognosis of NMIBC patients receiving BCG treatment. Furthermore, compared with the PSII and PISII, the ISII had better prognostic value, which might help select an optimal treatment schedule for patients with NMIBC. Of course, prospective and large-scale studies are still required for more representative samples with higher statistical power.

      Author contributions

      Conceptualization, DL and QY; formal analysis, DL and DF; funding acquisition, PH; investigation, DL, DF, FZ, RW, QY; methodology, QYand FZ; resources, DF; supervision, PH.; visualization, XS; writing-original draft, DL; writing-review & editing, DF and PH.

      Funding

      The study was supported by the Pillar Program from Department of Science and Technology of Sichuan Province ( 2018SZ0219 ) and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University ( ZY2016104 ).

      Ethical considerations

      The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics board of West China Hospital, Sichuan University (No. 20201045) and informed consent was taken from all the patients.

      CRediT authorship contribution statement

      Li Deng-xiong: Conceptualization, Formal analysis, Investigation, Writing – original draft. Yu Qing-xin: Methodology, Conceptualization, Investigation. Feng De-chao: Formal analysis, Writing – review & editing, Investigation, Resources. Zhang Fa-cai: Methodology, Investigation. Wu Rui-cheng: Investigation. Xu Shi: Visualization. Ping Han: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.

      Conflicts of Interest

      The authors declare no conflicts of interest.

      Acknowledgments

      None.

      Reference

        • Sung H
        • Ferlay J
        • Siegel RL
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J Clin. 2021; 71: 209-249https://doi.org/10.3322/caac.21660
        • EAU Guidelines
        Edn. presented at the EAU Annual Congress Amsterdam. 2022 (ISBN 978-94-92671-16-5)
        • Chang SS
        • Boorjian SA
        • Chou R
        • et al.
        Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline.
        J Urol. 2016; 196: 1021-1029https://doi.org/10.1016/j.juro.2016.06.049
        • Shi X
        • Feng D
        • Wei W
        A Systematic Review and Meta-Analysis Protocol of Chemoablation vs. Transurethral Resection of Bladder Tumor in Patients With Non-Muscle-Invasive Bladder Cancer.
        Front Surg. 2021; 8 (Published 2021 Nov 15)753547https://doi.org/10.3389/fsurg.2021.753547
        • Feng D
        • Li A
        • Hu X
        • et al.
        Comparative effectiveness of open, laparoscopic and robot-assisted radical cystectomy for bladder cancer: a systematic review and network meta-analysis.
        Minerva Urol Nefrol. 2020; 72: 251-264https://doi.org/10.23736/S0393-2249.20.03680-26
        • Feng D
        • Wang Z
        • Yang Y
        • et al.
        Incidence and risk factors of parastomal hernia after radical cystectomy and ileal conduit diversion: a systematic review and meta-analysis.
        Transl Cancer Res. 2021; 10: 1389-1398https://doi.org/10.21037/tcr-20-3349
        • Zhong JH
        • Huang DH
        • Chen ZY.
        Prognostic role of systemic immune-inflammation index in solid tumors: a systematic review and meta-analysis.
        Oncotarget. 2017; 8: 75381-75388https://doi.org/10.18632/oncotarget.18856
        • Bi H
        • Shang Z
        • Jia C
        • et al.
        Predictive Values of Preoperative Prognostic Nutritional Index and Systemic Immune-Inflammation Index for Long-Term Survival in High-Risk Non-Muscle-Invasive Bladder Cancer Patients: A Single-Centre Retrospective Study.
        Cancer Manag Res. 2020; 12 (Published 2020 Oct 1): 9471-9483https://doi.org/10.2147/CMAR.S259117
        • Akan S
        • Ediz C
        • Sahin A
        • et al.
        Can the systemic immune inflammation index be a predictor of BCG response in patients with high-risk non-muscle invasive bladder cancer?.
        Int J Clin Pract. 2021; 75: e13813https://doi.org/10.1111/ijcp.13813
        • Ke ZB
        • Chen H
        • Chen JY
        • et al.
        Preoperative abdominal fat distribution and systemic immune inflammation were associated with response to intravesical Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer.
        Clin Nutr. 2021; 40: 5792-5801https://doi.org/10.1016/j.clnu.2021.10.019
        • van Puffelen JH
        • Keating ST
        • Oosterwijk E
        • et al.
        Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer.
        Nat Rev Urol. 2020; 17: 513-525https://doi.org/10.1038/s41585-020-0346-4
        • Bisiaux A
        • Thiounn N
        • Timsit MO
        • et al.
        Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus calmette-guerin therapy in patients with superficial bladder cancer.
        J Urol. 2009; 181: 1571-1580https://doi.org/10.1016/j.juro.2008.11.124
        • Calais S
        • Paula V
        • Dário L
        • et al.
        Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more.
        Journal of Cancer Metastasis and Treatment. 2017; 3https://doi.org/10.20517/2394-4722.2017.25
        • Kamat AM
        • Briggman J
        • Urbauer DL
        • et al.
        Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin.
        Eur Urol. 2016; 69: 197-200https://doi.org/10.1016/j.eururo.2015.06.023
        • Humphrey PA
        • Moch H
        • Cubilla AL
        • et al.
        The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours.
        Eur Urol. 2016; 70: 106-119https://doi.org/10.1016/j.eururo.2016.02.028
      1. Amin MB, E.S., Greene FL, Byrd DR, et al. AJCC cancer staging manual. 8th ed.

        • Hanahan D.
        Hallmarks of Cancer: New Dimensions.
        Cancer Discov. 2022; 12: 31-46https://doi.org/10.1158/2159-8290.CD-21-1059
        • Okada F
        • Izutsu R
        • Goto K
        • et al.
        Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects.
        Cancers (Basel). 2021; 13: 921https://doi.org/10.3390/cancers13040921
        • Katayama S
        • Mori K
        • Pradere B
        • et al.
        Prognostic value of the systemic immune-inflammation index in non-muscle invasive bladder cancer.
        World J Urol. 2021; 39: 4355-4361https://doi.org/10.1007/s00345-021-03740-3
        • Zhao R
        • Shan J
        • Nie L
        • et al.
        The predictive value of the ratio of the product of neutrophils and hemoglobin to lymphocytes in non-muscular invasive bladder cancer patients with postoperative recurrence.
        J Clin Lab Anal. 2021; 35: e23883https://doi.org/10.1002/jcla.23883
        • Zhang W
        • Wang R
        • Ma W
        • et al.
        Systemic immune-inflammation index predicts prognosis of bladder cancer patients after radical cystectomy.
        Ann Transl Med. 2019; 7: 431https://doi.org/10.21037/atm.2019.09.02
        • Grossmann NC
        • Schuettfort VM
        • Pradere B
        • et al.
        Impact of preoperative systemic immune-inflammation Index on oncologic outcomes in bladder cancer patients treated with radical cystectomy.
        Urol Oncol. 2022; 40: 106.e11-106.e19https://doi.org/10.1016/j.urolonc.2021.10.006
        • Wang QH
        • Ji JL
        • Li H
        • et al.
        Preoperative Lymphocyte-to-monocyte Ratio Predicts Prognosis in Patients with Stage T1 Non-muscle Invasive Bladder Cancer.
        Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2019; 41: 622-629https://doi.org/10.3881/j.issn.1000-503X.11227