Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2021 May 14;16(5):e0248871. doi: 10.1371/journal.pone.0248871

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer

Sho Matsubara 1, Seiji Mabuchi 1,*, Yoshinori Takeda 1, Naoki Kawahara 1, Hiroshi Kobayashi 1
Editor: Julia Robinson2
PMCID: PMC8121307  PMID: 33989285

Abstract

Background

The systemic immune-inflammation index (SII), which is calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently attracted attentions as a prognostic indicator in patients with solid malignancies. In the current study, we retrospectively investigated the prognostic significance of pre-treatment SII among patients with endometrial cancer.

Method

Endometrial cancer patients treated at Nara medical university hospital between 2008 and 2018 were included in the current study. Receiver operating characteristic (ROC) curve was used to find the optimal SII cut-off values for 3-years progression free survival (PFS) and overall survival (OS). Then, the predictive abilities of SII and its superiority over neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were investigated. Kaplan-Meier method was used to calculate the OS and PFS rates, and log-rank test was used to compare the survival rate between two groups. Univariate and multivariate Cox regression analysis were performed to identify risk factors for PFS and OS.

Result

A total of 442 patients were included in the current study. The cut-off value of SII for predicting PFS and OS were defined by ROC analysis as 931 and 910, respectively. Univariate analyses showed that elevated SII was associated with significantly shorter survival (p <0.001 for both PFS and OS). Cox regression analyses revealed that an advanced FIGO stage (p <0.001 for both PFS and OS) and an elevated SII (p = 0.014 for PFS, p = 0.011 for OS) are the independent prognostic factors for survival. When SII was compared with NLR and PLR, SII showed greater area under curve for predicting survival.

Conclusion

The SII is an independent prognostic factor in endometrial cancer patients, allowing more precise survival estimation than PLR or NLR.

Introduction

Endometrial cancer is the second most common and the fourth leading cause of death due to gynecological cancer among women worldwide, and there are an estimated 382,069 new cases and 89,929 deaths attributed to endometrial cancer worldwide in 2018 [1]. In Japan, estimated 11,120 new cases and 2526 deaths were reported annually in 2017 [2,3]. The 5-year survival rate is 74–91%, 57%-66%, and 20–25% for patients with FIGO stage I-II, stage III, and stage IV disease, respectively [4].

Numerous studies have attempted to identify prognostic factors in patients with endometrial cancer. As a result, International Federation of Gynecologic and Obstetrics (FIGO) stage, the histologic subtypes and the grade of the tumor, positive peritoneal cytology and lymphovascular space invasion (LVSI) have been pointed out as prognostic factors [5–11]. However, most of these prognosticators can be available only after surgical treatment, and the ability of these risk factors to predict recurrence and estimate survival has been insufficient.

Inflammatory reactions in tumor microenvironment plays an important role in tumor development and progression [12,13]. As inflammation can stimulate granulopoiesis or thrombopoiesis, inflammatory indexes such as leukocytosis, neutrophilia, thrombocytosis, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) can serve as significant prognosticator in patients with solid malignancies including endometrial cancer [14,15]. Recently, a novel inflammatory index, the systemic immune-inflammation index (SII) based on peripheral neutrophil, platelet, and lymphocyte counts, was been found to be an useful prognosticator in cancer patients [16–30]. However, the prognostic significance of SII in endometrial cancer patients or its relative utility when compared with other inflammatory indexes has not been fully investigated [31,32]. In the current study, using clinical data obtained from 442 endometrial cancer patients, we investigated the prognostic significance of SII in endometrial cancer.

Material and method

Patients

This retrospective cohort study was approved by the Ethics Committee of Nara Medical University, and the analysis of the patient-derived data was carried out in accordance with the Declaration of Helsinki.

We generated a database of patients who were diagnosed with endometrial cancer from January 2008 to December 2018 at Nara medical university hospital. All patients signed the informed consent form. All patients routinely took blood examination before the initiation of treatment. Clinical information including age, body mass index (BMI), histological subtype, histological grade, FIGO stage, LVSI, peritoneal cytology, and pre-treatment blood examination results were collected from the database, and retrospectively reviewed.

Treatment and follow-up

Patients were staged according to the FIGO surgical staging criteria. If surgery was not possible especially in stage IV patients, patients were clinically staged instead. Almost all patients except for those with tumor invasion to pelvic organs or with systemic metastases (FIGO stage IV) were treated with surgery followed by adjuvant chemotherapy. Some patients who cannot be treated with chemotherapy because of poor general condition were treated only with surgery. The main surgical procedures consisted of total abdominal hysterectomy (TAH) or total laparoscopic hysterectomy (TLH), bilateral salpingo-oophorectomy (BSO), and pelvic lymphadenectomy. Patients who exhibited grade 3 endometrioid adenocarcinoma, tumor invasion more than 50% of the myometrium, non-endometrioid histology or extrauterine disease, paraaortic lymphadenectomy was also performed. In case with cervical stromal invasion, radical hysterectomy was employed instead of TAH/TLH. In the case of non-endometrioid histology, omentectomy was also performed. Postoperative adjuvant chemotherapy or radiotherapy was recommended for all patients who had any of the following risk factors for recurrence: over 50% myometrial invasion, cervical stromal invasion, extra-uterine disease, and high-risk histological type and grade (non-endometrioid, grade 3 endometrioid). The adjuvant chemotherapy includes triweekly cisplatin (50 mg/m2) plus doxorubicin (60 mg/m2) or triweekly paclitaxel (175 mg/m2) plus carboplatin (area under the curve: 5). When the patients had tumors invaded to pelvic organs or had systemic distant metastases (FIGO stage IV), personalized treatment either with chemotherapy, radiotherapy, or best supportive care were performed.

Follow-up was conducted one to three monthly for the first 36 months, 6-monthly for the next 24 months in outpatient clinic. Lesions suspected for recurrence were confirmed by histological or cytological diagnosis, whenever possible. In cases in which the histology or cytology of the recurrent lesion could not be assessed, the diagnosis of recurrence was made based on imaging studies.

Definitions of systemic inflammatory indexes and statistical analysis

The inflammatory indexes were calculated preoperative inflammatory indicators with the following formulas; SII = platelet counts × neutrophil counts/lymphocyte counts, NLR = neutrophil counts/lymphocyte counts, PLR = platelet counts/lymphocyte counts. In cases chemotherapy had been employed as a primary treatment, SII was calculated from the pretreatment inflammatory indicators.

Using cancer-specific death, cancer recurrence, and disease progression in 3-years as the end point, receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of SII. The cut-off value was based on the highest Youden index (i.e., sensitivity + specificity– 1). ROC curve analysis was also used to compare the usefulness of the three inflammatory indexes SII, NLR, PLR as prognostic factors. Pearson chi-square test was used to compare between groups. Kaplan-Meier method was used to calculate the overall survival (OS) and progression free survival (PFS) rates, and log-rank test was used to compare the survival rate between two groups. OS was defined as the time from the initiation of treatment to death of any cause, and PFS was defined as the time from the initiation of treatment until evidence of disease progression or death of any cause. Univariate and multivariate survival analysis were performed in order to identify independent risk factors for prognosis by using Cox regression analysis. Differences with P-values less than 0.05 were considered statistically significant. SPSS software (ver.25.0, SPSS Inc., Chicago, IL) and R software (ver.3.6.2, freely available from URL: https://www.r-project.org/) were used for the statistical analysis.

Result

Patients

A total of 442 endometrial cancer patients were included in the present study (Table 1). The median age was 59 years (range: 24–84). The median follow-up time was 47.5 months (range: 2–138). Three hundred and eleven patients (70.4%) had stage I, 38 (8.5%) had stage II, 56 (12.6%) had stage III and 37 (8.3%) had stage IV disease. Ninety six patients (21.7%) had non-endometrioid type histology, and 151 patients exhibited high histological grade.

Table 1. Clinicopathological characteristics of patients with endometrial cancer.

No. of Patients (n = 442) %
Age Mean ± SD (range) 59.0 ± 11.5 (24–84)
≦59 233 52.7
>59 209 47.3
BMI Mean ± SD (range) 23.3 ± 5.4 (15.1–47.8)
FIGO stage I 311 70.4
II 38 8.5
III 56 12.6
IV 37 8.3
Histological subtype Endometrioid 346 78.3
Non-endometrioid 96 21.7
Histological grade Grade 1 198 44.8
Grade 2 93 21.0
Grade 3 1 151 34.2
LVSI Positive 131 29.6
Negative 278 65.2
NA 13 2.9
Peritoneal cytology Positive 81 18.3
Negative 328 78.7
NA 13 2.9
Primary treatment Surgery alone 201 45.5
Surgery + adjuvant chemotherapy 218 49.3
Surgery + adjuvant radiotherapy 22 5.0
Chemotherapy alone 1 0.2
Radiotherapy alone 0 0
Open in a new tab

1: Grade 3 includes grade 3 endometrioid type and non-endometrioid type.

SD; standard deviation, BMI; body mass index, FIGO; Federation of Gynecology and Obstetrics, LVSI; lymphovascular space invasion, SII; systemic immune-inflammation index, NA; not available.

ROC analyses revealed that the optimal cut-off values of SII for predicting PFS and OS were 931 and 910, respectively (Fig 1). As shown in Table 2, an elevated SII (>931) was observed in 135 patients (30.5%), and was associated with advanced FIGO stage, non-endometrioid histology, higher tumor grade, LVSI, and positive peritoneal cytology. Similar results were obtained from the analysis in which a cut-off value was 910 was employed (S1 Table).

Fig 1. Clinical implications of SII in endometrial cancer patients.

Fig 1

Open in a new tab

A. ROC curves for progression-free survival (PFS) at 3-years. B, ROC curves for overall survival (OS) at 3-years.

Table 2. Correlations between SII for PFS and clinicopathological characteristics.

SII≤931 (n = 307) SII>931 (n = 135) p-value
Age ≦59 156 77 0.228
>59 151 58
FIGO stage I 239 72 <0.001
II 26 12
III 30 26
IV 12 25
Histological subtype Endometrioid 249 97 0.029
Non-endometrioid 58 38
Histological grade Grade 1 159 41 <0.001
Grade 2 62 31
Grade 3 1 86 63
LVSI Positive 84 47 0.001
Negative 219 79
NA 4 9
Peritoneal cytology Positive 47 34 <0.001
Negative 256 92
NA 4 9
Open in a new tab

1: Grade 3 includes grade 3 endometrioid type and non-endometrioid type.

PFS; progression free survival, SII; systemic immune inflammation index, FIGO; Federation of Gynecology and Obstetrics, LVSI; lymphovascular space invasion, NA; not available.

Correlation between the SII and the prognosis

During follow-up, cancer recurrence was observed in 74 patients (16.7%), 58 patients (13.1%) died of endometrial cancer and 2 patients died of other diseases. As shown in Fig 2, patients exhibiting higher SII showed significantly shorter PFS and OS than those exhibiting lower SII. Cox regression analyses revealed that an advanced FIGO stage (hazard ratio: 5.01; 95% CI: 3.06 to 8.19; p <0.001 for PFS, hazard ratio: 9.08; 95% CI: 4.83 to 17.03; p <0.001 for OS) and an elevated SII (hazard ratio: 1.71; 95% CI: 1.11 to 2.62; p = 0.014 for PFS, hazard ratio: 1.96; 95% CI: 1.16 to 3.30; p = 0.011 for OS) were the independent prognostic factors for endometrial cancer patients for both PFS and OS (Table 3).

Fig 2. Kaplan-Meier estimates of survival in endometrial cancer patients based on SII.

Fig 2

Open in a new tab

A, PFS. B, OS. Patients exhibiting higher SII showed significantly shorter PFS (p<0.001) and OS (p<0.001) than those exhibiting lower SII. The p-values were analyzed by log-rank test.

Table 3. Result of univariate and multivariate cox regression analysis for progression free survival and overall survival in endometrial cancer.

Variables PFS OS
Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis
HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value
FIGO stage Stage I, II 1 1 1 1
Stage III, IV 8.85 (5.79–13.53) <0.001 5.01 (3.06–8.19) <0.001 8.85 (5.78–13.53) <0.001 9.08 (4.83–17.03) <0.001
Histological subtype Endometrioid 1 1 1 1
Non-endometrioid 3.73 (2.48–5.63) <0.001 1.97 (1.08–3.57) 0.026 3.73 (2.48–5.63) <0.001 1.87 (0.93–3.75) 0.079
Histological grade Grade 1, 2 1 1 1 1
Grade 3 1 4.26 (2.78–6.52) <0.001 1.57 (0.84–2.91) 0.156 4.23 (2.78–6.52) <0.001 2.18 (1.03–4.62) 0.043
LVSI Negative 1 1 1 1
Positive 2.79 (1.85–4.20) <0.001 1.45 (0.92–2.30) 0.108 2.79 (1.85–4.20) <0.001 1.17 (0.67–2.01) 0.584
Peritoneal cytology Negative 1 1 1 1
Positive 2.64 (1.71–4.07) <0.001 1.18 (0.74–1.87) 0.484 2.64 (1.71–4.07) <0.001 0.82 (0.54–1.63) 0.824
SII ≤931 1 1
>931 2.58 (1.71–3.88) <0.001 1.71 (1.11–2.62) 0.014
≤910 1 1
>910 2.48 (1.65–3.74) <0.001 1.96 (1.16–3.30) 0.011
Open in a new tab

1: Grade 3 includes grade 3 endometrioid type and non-endometrioid type.

FIGO; Federation of Gynecology and Obstetrics, LVSI; lymphovascular space invasion, SII; systemic immune inflammation index, NA; not available, PFS; progression free survival, OS; overall survival, HR; hazard ratio, CI; confidence interval.

Comparison of SII with other systemic inflammatory indexes

Finally, using ROC curves, we compared the ability of various systemic inflammatory indexes to predict PFS and OS (Fig 3). As shown, although there is no significant statistical deference, SII showed larger AUC than NLR. Moreover, SII showed significantly larger AUC than PLR, indicating the superiority of SII when compare with other inflammatory indexes in this patient population (Table 4).

Fig 3. Comparison of the utility of the SII versus theta of the other inflammatory indexes.

Fig 3

Open in a new tab

A, ROC curves for 3-years PFS. B, ROC curves for 5-years PFS. C, ROC curves for 3-years OS. D, ROC curves for 5-years OS.

Table 4. Correlations between SII and other systemic inflammatory indexes.

OS PFS
AUC p-value (versus SII) AUC p-value (versus SII)
3-years SII 0.709 0.689
NLR 0.687 0.365 0.668 0.208
PLR 0.625 0.008 0.637 0.041
5-years SII 0.652 0.602
NLR 0.629 0.268 0.580 0.197
PLR 0.579 0.022 0.550 0.041
Open in a new tab

SII; systemic immune-inflammation index, OS; overall survival, PFS; progression free survival, AUC; area under curve, NLR; neutrophil-lymphocyte ratio, PLR; platelet-lymphocyte ratio.

Discussion

To our knowledge, this is the largest study that investigated the prognostic significance of SII in endometrial cancer patients (S2 Table). In our study population, when cut-off values of 931 and 910 were employed, elevated SII was observed in 30.5% and 32.1% of patients, respectively. An elevated SII was significantly associated with an advanced clinical stage, non-endometrioid histological subtype, higher histological grade, LVSI and positive peritoneal cytology, indicating the aggressive nature of endometrial cancer displaying elevated SII. In the survival analysis, SII was found to be a significant predictor for decreased PFS and OS in patients with endometrial cancer. We also found that the SII was a superior prognostic predictor to NLR and PLR in patients with endometrial cancer.

In endometrial cancer, 2 previous studies have investigated the prognostic significance of SII. As shown (S2 Table), both studies included relatively small number of patients, but produced conclusions were similar to ours. The consistent results obtained from these studies strongly indicate the prognostic significance of SII in endometrial cancer patients. However, as the cutoff value of SII differed between the studies, further multi-institutional investigations including larger number of patients are necessary.

The result obtained in the current study may have important clinical implication. By performing simple and low-cost peripheral blood examinations, we may be able to identify patients who have greater risk for developing recurrence. In our study population, elevated SII was detected in roughly 30% of patients. For these patients, careful post-treatment follow-up can be performed. Moreover, the results of our ROC analysis suggest that the prediction of recurrence can be significantly improved by assessing SII instead of PLR or NLR, allowing more precise survival estimation than PLR or NLR.

The underlying mechanisms responsible for the development of elevated SII in endometrial cancer patients and the subsequent increase in the aggressiveness of the disease remain unknown. However, previous studies have suggested that lymphocytes interplay in controlling tumor growth via secreting cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Thus, low lymphocyte counts may reflect the impaired host immunosurveillance, which might lead to a poor prognosis [33,34]. Moreover, as an elevated SII reflects a status of elevated neutrophil and platelet counts, we believe that factors that stimulate granulopoiesis and/or thrombopoiesis might also be involved in the mechanism responsible for the elevated SII in endometrial cancer patients. According to a recent study conducted by Yokoi et al, the tumor derived granulocyte colony-stimulating factor (G-CSF) induces leukocytosis in endometrial cancer patients and stimulates the production of interleukin-6 (IL-6) from tumor microenvironment and cause thrombocytosis [35]. As both neutrophils and platelets can stimulate cancer progression by enhancing tumor angiogenesis, tumor cells’ epithelial mesenchymal transition (EMT) via the production of vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP-9) and IL-6 or IL-8, it is possible that tumor become aggressive in patients with neutrophilia and thrombocytosis. [36–39]. We consider that future investigation of the underlying causative mechanism of elevated SII will aid the development of novel effective treatments for this type of endometrial cancer.

There are some limitations of this study. First, our study was conducted at a single institution. Second is the retrospective nature of this study, which is susceptible to bias in data selection and analysis. Third, we included only Japanese women with endometrial cancer in which increased BMI is rarely observed (mean BMI of the patients was 23.3). Thus, further investigations involving patients with wide range of BMI will be required. Fourth, although SII was found to be an independent predictor for decreased PFS and OS in patients with endometrial cancer in the multivariate analysis, the prognostic significance of SII was not investigated in studies in which arms (SII-high versus SII-low) were balanced. Fifth, we did not include comorbid conditions such as a diabetes or cardiovascular diseases, which may affect patient’s survival, as a prognostic variable in our univariate and multivariate analyses. Sixth, as this study is covering a long study period, changes in the choice of treatments might have affected the survival of patients included in the study. To eliminate these biases and validate the results from current study, future larger studies especially in a prospective randomized or a propensity score matching settings are required. Finally, in our multivariate analyses, the prognostic impact of FIGO stage was greater than SII (Table 3). However, whether it is reasonable to apply SII over FIGO stage or vice versa to estimate the prognosis of endometrial cancer patients remains unknown. Thus, the clinical application of SII in the survival estimation need to be further investigated in this patient population.

In conclusion, the presence of elevated SII at the time of initial diagnosis is an independent predictor of poor prognosis in endometrial cancer patients. Future validation study, especially in large scale prospective setting, is warranted so that SII will be widely used as a prognosticator in endometrial cancer patients.

Supporting information

S1 Table. Correlations between SII for OS and clinicopathological characteristics.

(DOCX)

Click here for additional data file. (18.1KB, docx)
S2 Table. Summary of investigations of the role of SII in endometrial cancer patients.

(DOCX)

Click here for additional data file. (16.3KB, docx)

Acknowledgments

The authors thank Dr. Mika Nagayasu, M.D., Dr. Ryuta Miyake, M.D., Dr. Masahide Nakatani, M.D., Dr. Haruki Nakamura, M.D., Dr. Shunsuke Onishi, M.D. for data collection.

Data Availability

There is an ethical restriction on sharing a de-identified data set, because the data contain potentially identifying patient information. However, data from this study are available upon request. Ethics Committee of Nara Medical University has imposed them. Contact information for a data requests is described bellow. Department of Obstetrics and Gynecology, Nara Medical University. Address: 840 Shijo-cho, Kashihara, Nara, 634-8522 Japan. Telephone: +81-744-29-8877 FAX: +81-744-23-6557 E-mail: obgynlab@naramed-u.ac.jp.

Funding Statement

The authors received no specific funding for this work. Thus, no funders had role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. 10.3322/caac.21492 [DOI] [PubMed] [Google Scholar]
  • 2.Japan Society of Obstetrics and Gynecology. Patient Annual Report for 2017. 2017. http://fa.kyorin.co.jp/jsog/readPDF.php?file=71/5/071050669.pdf, accessed on February 13, 2020.
  • 3.Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan (Vital Statistics of Japan). 2017. https://ganjoho.jp/reg_stat/statistics/dl/index.html#mortality, accessed on February 13, 2020.
  • 4.Creasman W, Odicino F, Maisonneuve P, Quinn M, Beller U, Benedet J, et al. Carcinoma of the corpus uteri. Int J Gynecol Obstet. 2006;95:105–143. [DOI] [PubMed] [Google Scholar]
  • 5.McMeekin S, Filiaci V, Thigpen T, Gallion H, Fleming G, Rodegers W, et al. Importance of histology in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study. Gynecol Oncol. 2007;106:16–22. 10.1016/j.ygyno.2007.04.032 [DOI] [PubMed] [Google Scholar]
  • 6.Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Rodenhuis C, et al. Surgery and post-operative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicenter randomized trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 2000;355:1404–1411. 10.1016/s0140-6736(00)02139-5 [DOI] [PubMed] [Google Scholar]
  • 7.Yazigi R, Piver M, Blumenson I. Malignant peritoneal cytology as an indicator in stage I endometrial cancer. Obstet Gynecol. 1983;62:359–362. 10.1097/00006250-198309000-00019 [DOI] [PubMed] [Google Scholar]
  • 8.Grimshaw R, Tupper W, Fraser R, Tompkins M, Jeffrey J. Prognostic value of peritoneal cytology in endometrial carcinoma. Gynecol Oncol. 1990;36:97–100. 10.1016/0090-8258(90)90116-3 [DOI] [PubMed] [Google Scholar]
  • 9.Sutton GP. The Significance of positive peritoneal cytology in endometrial cancer. Oncology. 1990;4:21–26. [PubMed] [Google Scholar]
  • 10.Havrilesky L, Cragun J, Calingaert B, Secord A, Valea F, Clarke-Pearson D, et al. The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage III a endometrial cancer. Gynecol Oncol. 2007;104:401–405. 10.1016/j.ygyno.2006.08.027 [DOI] [PubMed] [Google Scholar]
  • 11.Guntupalli S, Zigheloim I, Kizer N, Zhang Q, Powell M, Thaker P, et al. Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer. Gynecol Oncol. 2012;124:31–35. 10.1016/j.ygyno.2011.09.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–899. 10.1016/j.cell.2010.01.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ostan R, Lanzarini C, Pini E, Scurti M, Vianello D, Bertarelli C, et al. Inflammaging and Cancer: A Challenge for the Mediterranean Diet. Nutrients. 2015;7:2589–2621. 10.3390/nu7042589 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Cummings M, Merone L, Keeble C, Burland L, Grzelinski M, Sutton K, et al. Preoperative neutrophil:lymphocyte and platelet:lymphocyte ratios predict endometrial cancer survival. Br J Cancer. 2015;113:311–320. 10.1038/bjc.2015.200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ni L, Tao J, Xu J, Yuan X, Long Y, Yu N, et al. Prognostic values of pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in endometrial cancer: a systematic review and meta-analysis. Arch Gynecol Obstet. 2020;301:251–261. 10.1007/s00404-019-05372-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Hu B, Yang XR, Xu Y, Sun Y, Sun C, Guo W, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20:6212–6222. 10.1158/1078-0432.CCR-14-0442 [DOI] [PubMed] [Google Scholar]
  • 17.Geng Y, Shao Y, Zhu D, Zheng X, Zhou Q, Zhou W, et al. Systemic Immune-Inflammation Index Predicts Prognosis of Patients with Esophageal Squamous cell Carcinoma: A Propensity Score-matched analysis. Sci Rep. 2016;6:39482. 10.1038/srep39482 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Shao Y, Geng Y, Gu W, Ning Z, Huang J, Pei H, et al. Assessment of Lymph Node Ratio to Relapse the pN Categories System of Classification of the TNM System in Esophageal Squamous Cell Carcinoma. J Thorac Oncol. 2016;11:1774–1784. 10.1016/j.jtho.2016.06.019 [DOI] [PubMed] [Google Scholar]
  • 19.Passardi A, Scarpi E, Cavanna L, Dall’Agata M, Tassinari D, Leo S, et al. Inflammatory indexes as predictors of prognostic and bevacizumab efficiency in patients with metastatic colorectal cancer. Oncotarget. 2016;7:33210–33219. 10.18632/oncotarget.8901 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Hong X, Cui B, Wang M, Yang Z, Yang L, Xu Q. Systemic Immune-Inflammation Index Based on Platelet Counts and Neutrophil-Lymphocyte Ratio, Is Useful for predicting Prognosis in Small Cell Lung Cancer. Tohoku J Exp Med. 2015;236:297–304. 10.1620/tjem.236.297 [DOI] [PubMed] [Google Scholar]
  • 21.Berardi R, Santoni M, Rinaldi S, Bower M, Tiberi M, Morgese F, et al. Pre-treatment systemic immune-inflammation represents a prognostic factor in patients with advanced non-small cell lung cancer. Ann Transl Med. 2019;7:572. 10.21037/atm.2019.09.18 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Whang Q, Zhu D. The prognostic value of systemic immune-inflammation index(SII) in patients after radical operation for carcinoma of stomach in gastric cancer. J Gastrointest Oncol. 2019:10;965–978. 10.21037/jgo.2019.05.03 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Chen L, Yan Y, Zhu L, Cong X, Li S, Song S, et al. Systemic Immune-Inflammation Index as a useful prognostic indicator predicts survival in patients with advanced gastric cancer treated with neoadjuvant chemotherapy. Cancer Manag Res. 2017;9:849–897. 10.2147/CMAR.S151026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Murthy P, Zanati M, Abbas A, Rieser C, Behary N, Lotze M, et al. Prognostic Value of the Systemic Immune-Inflammation Index (SII) After Neoadjuvant Therapy for Patients with Resected Pancreatic Cancer. Ann Surg Oncol. 2020;27:898–906. 10.1245/s10434-019-08094-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Liu J, Shi Z, Bai Y, Liu L, Cheng K. Prognostic significance of systemic immune-inflammation index in triple-negative breast cancer. Cancer Manag Res. 2019;11:4471–4480. 10.2147/CMAR.S197623 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Zhang W, Wang R, Ma W, Wu Y, Maskey N, Guo Y, et al. Systemic immune-inflammation index predicts prognosis of bladder cancer patients after radical cystectomy. Ann Transl Med. 2019;7:431. 10.21037/atm.2019.09.02 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Liang R, Li J, Tang X, Liu Y. The prognostic role of preoperative systemic immune-inflammation index and albumin/globulin ratio in patients with newly diagnosed high-grade glioma. Clin Neurol Neurosurg. 2019;184:105397. 10.1016/j.clineuro.2019.105397 [DOI] [PubMed] [Google Scholar]
  • 28.Mirli C, Paydas S, Kapukaya T, Yilmaz A. Systemic immune-inflammation index predicting survival outcome in patients with classical Hodgikin lymphoma. Biomark Med. 2019;13;1565–1575. 10.2217/bmm-2019-0303 [DOI] [PubMed] [Google Scholar]
  • 29.Yilmaz A, Mirili C, Bilici M, Tekin S. A novel predictor in patients with gastrointestinal stromal tumors: Systemic immune-inflammation index(SII). J BUON. 2019;24:2127–2135. [PubMed] [Google Scholar]
  • 30.Huang H, Liu Q, Zhu L, Zhang Y, Lu X, Wu Y, et al. Prognostic Value of Preoperative Systemic Immune-Inflammation Index in Patients with Cervical Cancer. Sci Rep. 2019;9:3284. 10.1038/s41598-019-39150-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Holub K, Busato F, Gouy S, Sun R, Pautier P, Genestie C, et al. Analysis of Systemic Inflammatory Factors and Survival Outcomes in Endometrial Cancer Patients Staged I-III FIGO and Treated with Postoperative External Radiotherapy. J Clin Med. 2020;12;9:1441. 10.3390/jcm9051441 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Mirili C, Bilici M. Inflammatory prognostic markers in endometrial carcinoma: Systemic immune-inflammation index and prognostic nutritional index. Med Sci Discov. 2020;7, 351–359. [Google Scholar]
  • 33.Ogiya R, Niikura N, Kumaki N, Bianchini G, Kitano S, Iwamoto T, et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci. 2016;107:1730–1735. 10.1111/cas.13101 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ferrone C, Dranoff G. Dual roles for immunity in gastrointestinal cancers. J Clin Oncol. 2010;28:4045–4051. 10.1200/JCO.2010.27.9992 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Yokoi E, Mabuchi S, Komura N, Shimura K, Kuroda H, Kozasa K, et al. The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations. Oncoimmunology. 2019;8.e1662708. 10.1080/2162402X.2019.1662708 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Tan K, Chong S, Wong F, Evrard M, Tan S, Keeble J, et al. Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood. 2013;122:3666–3677. 10.1182/blood-2012-11-466532 [DOI] [PubMed] [Google Scholar]
  • 37.Kusumanto Y, Dam W, Hospers G, Meijer C, Mulder N. Platelets and granulocytes, in particular the neutrophils, from important compartments for circulating vascular endothelial growth factor. Angiogenesis.2003;6:283–287. 10.1023/B:AGEN.0000029415.62384.ba [DOI] [PubMed] [Google Scholar]
  • 38.Block MS, Markovic SN. The tumor/immune interface: clinical evidence of cancer immunosurveillance, immunoediting and immunosubversion. Am J Immunol. 2009;5:29–49. [Google Scholar]
  • 39.Stone R, Nick A, McNeish I, Balkwill F, Han H, Bottsford-Miller J, et al. Paraneoplastic Thrombocytosis in Ovarian Cancer. N Engl J Med. 2012;366:610–618. 10.1056/NEJMoa1110352 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Gayle E Woloschak

25 Aug 2020

PONE-D-20-05050

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer

PLOS ONE

Dear Dr. Mabuchi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Minor revisions were suggested by both reviewers.  Please see the comments below.

Please submit your revised manuscript by Oct 09 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3.Thank you for stating the following financial disclosure:

 [NO - Include this sentence at the end of your statement: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.].

At this time, please address the following queries:

  1. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

  2. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

  3. If any authors received a salary from any of your funders, please state which authors and which funders.

  4. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Additional Editor Comments (if provided):

Minor revisions were suggested by both reviewers.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Only question I'd have is the unbalanced arms. The derived systemic immune index is significantly different in for patients in different stages and grades. Would the index still be signifiicant if the arms were balanced with a propensity score matching?

Reviewer #2: This is an interesting manuscript that builds on evolving body of evidence driving toward improved indices to estimate survival after a cancer diagnosis. The index selected has been evaluated in a larger body of evidence, but not specifically for endometrial -a disease wherein survival is quite high in comparison to other cancers.

A few considerations:

Abstract -

while SII may have been determined to be an independent risk factor for survival, FIGO stage was by for the strongest predictor and this should be acknowledged in the abstract.

Overall

1. the sample was predominantly women with early disease and highly treatable endometrioid disease - yet "all patients were treated with surgery AND chemotherapy" -were women who only underwent hysterectomy excluded?

2. the mean BMI was within normal limits - this seems very unusual for endometrial cancer. The discussion should include a description and related context for interpreting the findings in countries where obesity is the major driver of disease risk. At minimum generalizability of the findings needs to be addressed more robustly.

3. Do you have data on co-morbid conditions such as diabetes? CVD? that may influence survival?

4. how readily assessed are the markers of the SII contstruct? in other words, is it reasonable to apply these over FIGO stage to estimate prognosis -or would it require additional measures be routinely assessed clinically? more clinical context to the application of these measures would be important.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 14;16(5):e0248871. doi: 10.1371/journal.pone.0248871.r002

Author response to Decision Letter 0

2 Sep 2020

Responses to Reviewer #1

Comment 1:

Only question I'd have is the unbalanced arms. The derived systemic immune index is significantly different in for patients in different stages and grades. Would the index still be signifiicant if the arms were balanced with a propensity score matching?

Response:

Thank you for a reviewer’s thoughtful comment. Although SII was found to be an independent predictor for decreased PFS and OS in patients with endometrial cancer in the multivariate analysis, the prognostic significance of SII was not investigated in studies in which arms (SII-high versus SII-low) were balanced. Thus, to validate the results from current study, future studies especially in a prospective randomized or a propensity score matching settings are required. We have described this in lines 267-269 of the revised manuscript.

 

Responses to Reviewer #2

Comment 1:

While SII may have been determined to be an independent risk factor for survival, FIGO stage was by for the strongest predictor and this should be acknowledged in the abstract.

Response:

As suggested, we have indicated this in the Abstract.

Comment 2:

The sample was predominantly women with early disease and highly treatable endometrioid disease - yet "all patients were treated with surgery AND chemotherapy" -were women who only underwent hysterectomy excluded?

Response:

Thank you for the reviewer’s comment. We have corrected the wordings (lines 108-111 of the revised manuscript).

Comment 3:

The mean BMI was within normal limits - this seems very unusual for endometrial cancer. The discussion should include a description and related context for interpreting the findings in countries where obesity is the major driver of disease risk. At minimum generalizability of the findings needs to be addressed more robustly.

Response:

I agree with the reviewer’s comment. It has been generally accepted that high BMI is associated with increased risk of endometrial cancer development. However, BMI of the Japanese women with endometrial cancer is not so high. For example, in a study conducted by Honda T, et al, roughly 70% of Japanese endometrial cancer patients had BMI<25 (Int J Womens Health. 2012;4:207-12.), which is consistent with our study. We think the prognostic significance of SII need to be further investigated in larger studies involving patients with wide range of BMI. We have described this as a limitation of the current study in lines 258-260 of the revised manuscript.

Comment 4:

Do you have data on co-morbid conditions such as diabetes? CVD? that may influence survival?

Response:

Thank you for a reviewer’s thoughtful comment. We did not include comorbid conditions such as a diabetes or cardiovascular diseases, which may affect patient’s survival, as a prognostic variable in our univariate and multivariate analyses. We have described this as a limitation of the current study in lines 263-265 of the revised manuscript.

Comment 5:

How readily assessed are the markers of the SII contstruct? in other words, is it reasonable to apply these over FIGO stage to estimate prognosis -or would it require additional measures be routinely assessed clinically? more clinical context to the application of these measures would be important.

Response:

In our multivariate analyses, the prognostic impact of FIGO stage was greater than SII (Table 3). However, whether it is reasonable to apply SII over FIGO stage or vice versa to estimate the prognosis of endometrial cancer patients remains unknown. Thus, we believe that the clinical application of SII in the survival estimation need to be further investigated in this patient population. We have described this as a limitation of the current study in lines 269-273 of the revised manuscript.

Attachment

Submitted filename: Response to Reviewer.docx

Click here for additional data file. (21.2KB, docx)

Decision Letter 1

Gayle E Woloschak

4 Dec 2020

PONE-D-20-05050R1

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer

PLOS ONE

Dear Dr. Mabuchi:

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Specific recommendations are listed below as minor revisions.

Please submit your revised manuscript by Jan 18 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Gayle E. Woloschak, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Some minor revisions are suggested.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: Addtional comments to the authors:

This is an interesting analysis of SII as potential pre-treatment predictor for survival in cohort of endometrial cancer patients.

Contrary to author’s statement as being the first study to evaluate SII in endometrial cancer, there are at least 2 published studies and these should be included in the discussion. Mirili et al (n=101) had SSI cutoff value of 1035.9 and concluded high SII, as well as PLR, NLR is associated with decreased OS. Holub et al evaluated SII, NLR, MLR and corresponding survival in endometrial cancer. Optimal cut-off was 1100.0 in this study, of which 19.4% (n=30) of patients were included. SSI was independent predictor for OS, but not for PFS or cancer specific survival.

Recent meta-analyses (Ji and Wang; Han et al) evaluating SII in gynecologic cancer also report few studies demonstrating SII correlation with decreased survival in ovarian, cervical and breast cancer, but none included endometrial cancer.

Comments:

- As previous reviewer commented, the SSI low and SSI high groups are imbalanced. Inherent limitation of a retrospective study, and the authors mention this limitation in revised manuscript. But I am concerned that this imbalance is linked to the observed statistically significant difference.

- Would be interesting to see the numbers of pts who received chemo, radiation in Table 1.

Minor comments:

- Line 103: Pre-treatment routine blood work is defined as when? Before surgery or before adjuvant therapy?

- Line 108: Clinically staged? Standard for endometrial cancer is surgical staging.

References:

Mirili, C.; Bilici, M. Inflammatory prognostic markers in endometrial carcinoma: Systemic immune-inflammation index and prognostic nutritional index. Med. Sci. Discov. 2020, 7, 351–359.

Holub K, Busato F, Gouy S, Sun R, Pautier P, Genestie C, Morice P, Leary A, Deutsch E, Haie-Meder C, Biete A, Chargari C. Analysis of Systemic Inflammatory Factors and Survival Outcomes in Endometrial Cancer Patients Staged I-III FIGO and Treated with Postoperative External Radiotherapy. J Clin Med. 2020 May 12;9(5):1441. doi: 10.3390/jcm9051441. PMID: 32408668; PMCID: PMC7291051.

Ji Y, Wang H. Prognostic prediction of systemic immune-inflammation index for patients with gynecological and breast cancers: a meta-analysis. World J Surg Oncol. 2020 Aug 7;18(1):197. doi: 10.1186/s12957-020-01974-w. PMID: 32767977; PMCID: PMC7414550.

Han X, Liu S, Yang G, Hosseinifard H, Imani S, Yang L, Maghsoudloo M, Fu S, Wen Q, Liu Q. Prognostic value of systemic hemato-immunological indices in uterine cervical cancer: A systemic review, meta-analysis, and meta-regression of observational studies. Gynecol Oncol. 2020 Oct 19:S0090-8258(20)34019-1. doi: 10.1016/j.ygyno.2020.10.011. Epub ahead of print. PMID: 33092868.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 14;16(5):e0248871. doi: 10.1371/journal.pone.0248871.r004

Author response to Decision Letter 1

8 Dec 2020

Responses to reviewers

Comment 1: Would be interesting to see the numbers of pts who received chemo, radiation in Table 1.

Response: As suggested, we have included the numbers of patients who received chemotherapy or radiotherapy in the revised Table 1.

Comment 2: Line 103: Pre-treatment routine blood work is defined as when? Before surgery or before adjuvant therapy?

Response: As stated in the title, we have investigated the “Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer”. However, as the reviewer pointed, the timing of the blood test has not been defined in the “Methods”. We now defined it in the revised manuscript (lines 115-118).

Comment 3: Line 108: Clinically staged? Standard for endometrial cancer is surgical staging.

Response: Thank you for the reviewer’s thoughtful comment. As pointed, the standard for endometrial cancer is surgical staging. We also do surgical staging for endometrial cancer patients. However, if surgery isn't possible especially in stage IVB patients, patients were clinically staged instead. Clinical staging in such patients are allowed globally. Clinical staging has been based on the results of a physical exam, biopsy, and imaging tests. We have changed the wording regarding the staging (lines 93-94 of the revised manuscript).

Comment 4: References

Responses: Thank you for a suggestion regarding the recent researches about SII in endometrial cancer. When we submitted our manuscript to PLOS one in Feb 2020, no reports have been published. Thus, in line 75-76 of the original manuscript, we have stated “the prognostic significance of SII in endometrial cancer patients or its relative utility when compared with other inflammatory indexes has never been investigated”. Moreover, in lines 220-221 of the revised manuscript, we stated “To our knowledge, this is the first study that investigated the prognostic significance of SII in endometrial cancer patients”. However, the time has passed, and situation have been changed. As suggested, we have changed the wordings (in lines 197-198 and 206-211 of the revised manuscript), and included recent researches about SII in endometrial cancer in the “References” and a “Supplemental Table 2”.

Attachment

Submitted filename: Responses to reviewer.docx

Click here for additional data file. (16.1KB, docx)

Decision Letter 2

Julia Robinson

8 Mar 2021

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer

PONE-D-20-05050R2

Dear Dr. Mabuchi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Julia Robinson

Staff Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #4: Yes: David Scott Miller

Acceptance letter

Julia Robinson

23 Mar 2021

PONE-D-20-05050R2

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer

Dear Dr. Mabuchi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Julia Robinson

Staff Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Correlations between SII for OS and clinicopathological characteristics.

    (DOCX)

    Click here for additional data file. (18.1KB, docx)
    S2 Table. Summary of investigations of the role of SII in endometrial cancer patients.

    (DOCX)

    Click here for additional data file. (16.3KB, docx)
    Attachment

    Submitted filename: Response to Reviewer.docx

    Click here for additional data file. (21.2KB, docx)
    Attachment

    Submitted filename: Responses to reviewer.docx

    Click here for additional data file. (16.1KB, docx)

    Data Availability Statement

    There is an ethical restriction on sharing a de-identified data set, because the data contain potentially identifying patient information. However, data from this study are available upon request. Ethics Committee of Nara Medical University has imposed them. Contact information for a data requests is described bellow. Department of Obstetrics and Gynecology, Nara Medical University. Address: 840 Shijo-cho, Kashihara, Nara, 634-8522 Japan. Telephone: +81-744-29-8877 FAX: +81-744-23-6557 E-mail: obgynlab@naramed-u.ac.jp.

    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES