Systemic Immune-Inflammation Index Is a Prognostic Predictor in Patients with Intrahepatic Cholangiocarcinoma Undergoing Liver Transplantation

Background It was reported that systemic immune inflammation index (SII) was related to poor prognosis in a variety of cancers. We aimed to investigate the ability of the prognostic predictors of SII in patients with intrahepatic cholangiocarcinoma (iCCA) undergoing liver transplantation (LT). Methods The 28 iCCA patients who underwent LT at our hospital between 2013 and 2018 were reviewed. Kaplan–Meier survival curves and Cox regression analyses were used to evaluate the prognostic significance of SII. Patients were divided into the high and low SII groups according to the cut-off value. Results The 1-, 3-, and 5-year OS rates were significantly lower in the high SII group (85.7%, 28.6%, and 21.4%, respectively) than in the low SII group (92.9%, 71.4%, and 57.2%, respectively; P = 0.009). The 1-, 3-, and 5-year RFS rates were, respectively, 57.1%, 32.7%, and 21.8% in the high SII group and 85.7%, 61.1%, and 61.1% in the low SII group (P = 0.021). SII ≥ 447.48 × 109/L (HR 0.273, 95% CI 0.082–0.908; P = 0.034) was an independent prognostic factor for OS. Conclusions Our results showed that SII can be used to predict the survival of patients with iCCA who undergo LT.


Introduction
Cholangiocarcinoma (CCA) is a rare malignant tumor with an incidence of less than 2/100,000 persons [1]. CCA is classified into several subtypes. iCCA accounts for 8-10% of biliary tract cancers [2]. The incidence of iCCA has been increasing worldwide over the last 3 decades, which may be related to primary sclerosing cholangitis, viral hepatitis, or chemical exposure [3]. Because of the poor long-term outcomes, iCCA is usually a contraindication for LT [4]. However, data from several studies have reported poor outcomes in patients with iCCA after transplantation [5]. Thus, many centers consider iCCA to be a contraindication to liver transplantation typically [6]. Despite the controversy, several studies have proposed that LT may provide accept-able long-term survival in selected patients with iCCA [7,8]. Therefore, it is necessary to establish appropriate criteria to select the right patients for liver transplantation. The current criteria for evaluating liver transplantation, such as the Milan criteria and Hangzhou criteria, that are effective for hepatocellular carcinoma (HCC) patients are not useful for evaluating patients with iCCA.
There is sufficient evidence that inflammation is related to tumor progression [9,10]. It was reported that inflammatory cells such as lymphocytes and platelets change the tumor microenvironment play an important role in promoting the proliferation, invasion, and migration of tumors. Inflammation-based scores, including PLR, PNI, and SII, have been reported to be useful prognostic biomarkers for various cancers [11][12][13][14]. SII has been proved to be a prognostic predictor for several cancers. However, it remains unclear whether there is a correlation between preoperative SII and prognosis in patients with iCCA undergoing LT. The purpose of this study was to explore the prognostic value of SII in patients with iCCA undergoing LT.

Methods
The 28 patients who received liver transplantation for iCCA at the First Affiliated Hospital, Sun Yat-Sen University (Guangzhou, China), from 2013 to 2018 were retrospectively reviewed. The diagnosis was confirmed by medical imaging and pathological examination of tissue specimens. Clinical characteristics extracted from the medical records. Patients were followed monthly for the first 6 months. This study only included patients with iCCA at the explant. Patients with mixed iCCA + HCC (in the same or different nodule) were excluded from the study.
All tumor patients including iCCA on the waiting list evaluated for extrahepatic metastasis were evaluated. Patients with an expected waiting list time of over 6 months could have been treated with transarterial chemoembolization (TACE), ablation as a bridge to LT. In addition to TACE and ablation, patients with iCCA diagnosed preoperatively received chemotherapy based on gemcitabine and cisplatin.
Independent χ 2 tests were used to compare categorical variables. Continuous variables were compared using t -tests. Survival curves were analyzed using the Kaplan-Meier method. The Cox regression analysis was used for univariate and multivariate analyses. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to examine the predictive value of the proposed model. All statistical analyses were performed using SPSS version 19.0 statistical software (SPSS, Chicago, IL, USA). P values < 0.05 were considered statistically significant.
All organs came from voluntary donations from citizens; no organs from executed prisoners (even with his/her consent) were used involved. The study was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University and was performed in accordance with the Declaration of Istanbul. All protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Results
A total of 28 consecutive adult liver transplant patients with iCCA were included in the analysis. Clinical characteristics are summarized in Table 1. Patients diagnosed with iCCA received adjuvant therapy, with gemcitabine and cisplatin, and only a subset of patients received TACE and ablation for pretransplant locoregional therapy.
The ROC curves of SII, NLR, and PLR indicated that 447.48, 2.92, and 106.62 were the optimal cut-off values.
Univariate analysis revealed CEA level, tumor recurrence, SII, PLR, and NLR to be significant prognostic factors for OS. Results of multivariate analysis showed that SII ≥ 447:48 × 10 9 /L was revealed to be an independent predictor

Discussion
Compared with HCC, iCCA has a higher recurrence rate and a worse prognosis. As such, liver transplantation for iCCA is highly controversial. Because of high recurrence rates and poor long-term survival, liver transplantation for iCCA has been abandoned in most transplantation centers. While the indications for liver transplantation for iCCA are controversial. In 2016, Sapisochin et al. [15] conducted a multicenter study that the advanced group had a higher 5-year recurrence rate than the very early iCCA group (61% vs. 15%, respectively) and lower 5-year OS (45% vs. 65%, respectively). Therefore, appropriate selection criteria are required to ensure a better prognosis of patients undergoing liver transplantation for iCCA. At present, there is no relevant study to explore the predictive value of SII in patients with iCCA for LT. In this study, patients who underwent LT for iCCA and demonstrated that a high SII (≥447:48 × 10 9 /L) significantly correlated with poorer prognosis. As mentioned earlier, some studies have shown that inflammation factors are associated with prognosis in patients with cancer [16][17][18]. SII is widely accepted to be a new predictive marker to predict the prognosis of several types of cancer [19][20][21]. However, there are few studies on the prognosis of SII and iCCA. Although SII has been confirmed to be related to the prognosis of iCCA, the mechanism is not clear. SII is a systemic inflammatory marker, which can predict the prognosis of tumor from the level of inflammatory and immune. It has been reported that poor prognosis are concomitant with some inflammatory markers, such as NLR and PLR [22,23]. Gomez et al. and Chen et al. reported that iCCA patients with a high preoperative NLR are related to poor prognosis [22,24]. Chen et al. also confirmed that high PLR was related to poor prognosis [25].
The number of neutrophils in patients with malignant tumors increases plays an important role in the development of tumors [26][27][28]. It is reported that lymphocytes can  3 Mediators of Inflammation mediate tumor regression effectively. The mechanism of which was realized by secreting cytokines and inducing cytotoxic cell death [29,30]. In patients with intrahepatic cholangiocarcinoma, elevated NLR was independently associated with poor prognosis [31]. Platelets and neutrophils can secrete vascular endothelial growth factor (VEGF), which is important in tumor progression [32]. It has been shown that tumors are infiltrated by various lymphocytes, which is related to the progress of tumor [33,34]. Immunooncology has become a promising approach in the field of new  Mediators of Inflammation anticancer drug development [35,36]. PD-L1 and HHLA2 are potential immunotherapeutic targets for iCCA patients [37,38]. This study has several limitations. First, this was a retrospective, single-center analysis with a small number of patients. Second, SII was a dynamic index in the process of treatment and could be affected by unidentified infection and hepatitis B infection and so on.
In conclusion, our study suggests that preoperative SII is a simple and useful predictor of prognosis, which will help to select more suitable iCCA patients for liver transplantation and improve the prognosis of patients with cholangiocarcinoma after liver transplantation.

Data Availability
The data used to support the findings of this study have not been made available because of local ethical guidelines.

Conflicts of Interest
The authors have declared no conflict of interest.

Authors' Contributions
A Ren and Y Ma are responsible for the conception and design. Y Ma obtained administrative support. A Ren and Z Li are involved in the provision of study materials or patients. Z Li, X Zhang, and P Cheng collected and assembled the data. A Ren, Z Li, P Cheng, and X Zhang are responsible for the data analysis and interpretation. All authors are involved in the manuscript writing. All authors approved the final manuscript.