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Introduction Pancreatic cancer is the fifth most frequently diagnosed cancer worldwide and is the fourth leading cause of cancer-related death [1]. Curative resection for pancreatic cancer provides the best opportunity of prolonged survival, with a reported overall 5-year survival after curative resection of 15%-20%. However, only 10%-20% of patients with pancreatic cancer are eligible for curative resection [2, 3]. The current gold standard therapy is curative resection followed by adjuvant chemotherapy. Recently, a number of reports have suggested the existence of a close association between the systemic inflammatory response and the prognosis in cancer patients [4-11]. Exacerbation of inflammation leads to the inhibition of apoptosis, promotion of angiogenesis and DNA damage, and promotes cancer growth and metastasis [12]. Numerous studies have reported associations between the values of several markers of the systemic inflammatory response, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and the Glasgow prognostic score (GPS), and the prognosis in pancreatic cancer patients [4, 6, 7, 13, 14]. However, in most of these reported studies, the sample sizes were rather small and both patients who received/did not receive resection followed by adjuvant chemotherapy were enrolled. Although systemic inflammatory markers are easily measurable, they are more likely to be affected by the presence of infection, however, in most of these reported studies, the effect of employing biliary drainage prior to surgery 1 was not investigated [6, 15, 16]. Therefore, the relationship between the prognosis of pancreatic cancer and systemic inflammatory markers remains under debate. The aim of this study was to determine the relationship between several systemic inflammatory markers and the prognosis of pancreatic cancer patients who received curative resection followed by adjuvant chemotherapy. Moreover, this study was performed to determine the relationship between the direction of change of the NLR after one cycle of adjuvant chemotherapy and the response to adjuvant chemotherapy. Methods Study Design The data of 197 pancreatic cancer patients in our database who underwent potentially curative resection (R0 or R1) at the National Cancer Center Hospital East between January 2009 and January 2015 were retrospectively reviewed. Of these, we excluded 57 patients for the following reasons: neoadjuvant chemotherapy or chemoradiotherapy (26 patients), evidence of infection (3 patients), resection with macroscopic residual tumor (R2) (2 patients), lost to follow-up (16 patients), histological type other than tubular adenocarcinoma, papillary adenocarcinoma and poorly differentiated adenocarcinoma (7 patients), other cause of death (3 patients). In addition, 30 patients who did not receive adjuvant chemotherapy following tumor resection were also excluded. Finally, 2 the data of the remaining 110 patients were analyzed. The resected specimens were histopathologically classified according to the International Union Against Cancer (UICC) TNM classification (7th edition). In regard to the adjuvant chemotherapy administered after the curative resection, 47 patients (42.7%) received gemcitabine monotherapy, 54 (49.1%) received S-1 (mixture of tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid) monotherapy, and 9 (8.2%) received combined gemcitabine plus S-1 chemotherapy. Peripheral blood samples were collected from the patients within 7 days of the tumor resection surgery. The laboratory data, including the neutrophil, lymphocyte and platelet counts, and serum levels of albumin (Alb), C-reactive protein (CRP) and carbohydrate antigen (CA) 19-9, were obtained from the medical records. The NLR, PLR and GPS, well known systemic inflammatory markers, were evaluated in this study. The NLR was calculated as the neutrophil count divided by the lymphocyte count. The PLR was calculated as the platelet count divided by the lymphocyte count. The GPS was calculated from the serum CRP and Alb levels, as follows: patients with both an elevated serum CRP level (>0.3mg/dl) and hypoalbuminemia (<3.5g/ml) were allocated a score of 2, patients with only one of these laboratory abnormalities were allocated a score of 1, and patients with neither of these abnormalities were allocated a score of 0. The timings of collection of the blood samples for determination of the direction of change of the NLR after adjuvant chemotherapy were within 2 days before the start of adjuvant chemotherapy and after one cycle of adjuvant chemotherapy. The change 3 in the NLR was calculated from the NLR determined after one cycle of adjuvant chemotherapy divided by the NLR before the start of adjuvant chemotherapy: a value>1 was defined as NLR increase and a value<1 was defined as NLR decrease. To determine the optimal cutoff value of the NLR for prediction of the overall survival (OS), we compared the OS rates using cutoff values of 2.0, 2.5, 3.0 and 3.5. The results of the above analysis conducted by the Kaplan-Meier method and the log-rank test yielded an NLR of 3.0 as the optimal cutoff value for predicting the survival rate. The cutoff value of the PLR has been reported previously to be 150 [15]. Pancreatic fistula formation was evaluated according to the classification of the International Study Group of Pancreatic Fistula [17]. Complications other than pancreatic fistula were classified according to the definition proposed by Dindo et al [18]. Only complications of grade 2 severity or over were recorded. The primary end point was the OS. Survival time was calculated from the date of surgery to the date of the last follow-up or death. The median follow-up period was 23 months (range, 5-70 months). The study was conducted with the approval of the Research Ethics Committee of the National Cancer Center Hospital. Statistical Analysis 4 The data are presented as medians and ranges. Time-to-event variables were calculated by the Kaplan-Meier method and compared by the log-rank test. The Cox regression model was used for the univariate analysis. Variables identified as having a significant prognostic value in the univariate analysis were entered into the multivariate Cox proportional hazards model. The Mann-Whitney U test was used to compare the relationship between the presence/absence of preoperative biliary drainage or direction of change of the NLR with chemotherapy and other variables. All statistical analyses were conducted using the JMP® 11 software (SAS Institute Inc., Cary, NC, USA). Results Patient characteristics The median age of the 110 patients was 68.5 years. There were 72 (65.5%) men and 38 (34.5%) women. The number of patients who received preoperative biliary drainage was 38 (34.5%). In regard to the surgical procedure performed for resection of the pancreatic cancer, 76 (69.1%) patients underwent pancreatoduodenectomy, 31 (28.2%) underwent distal pancreatectomy, and 3 (2.7%) underwent total pancreatectomy. The median postoperative hospital stay was 13 days. Of the 110 patients, 38 (28.2%) developed postoperative complications and 18 (16.4%) pancreatic fistula formation (≥Grade B). The demographics, tumor characteristics, and systemic inflammatory marker levels in the study patients are shown in Table 1. A total of 101 (91.8%) patients were classified as 5 having tubular adenocarcinoma. The number of patients with a positive nodal status was 77 (70%). Because all the patients with a positive nodal status were categorized into stage IIB or more, we treated the two synonymously. There were 101 (91.8%) patients with no residual tumor (R0) after surgery and 9 (8.2%) with microscopic residual tumor (R1) after surgery. The median interval to initiation of adjuvant chemotherapy was 53 days. Comparison of the clinical variables in relation to the OS The median survival time of the patients was 40 months (interquartile range, 30-47months). The univariate Cox regression analysis revealed an increase of the serum CA19-9 levels, except in cases of tubular adenocarcinoma, disease stage IIB or more, and NLR increase as significant prognostic factors for the OS (Table 2). In this study, the NLR, PLR and GPS were not identified as significant predictors of the OS. The multivariate analysis carried out using the Cox regression model identified, only the direction of change of the NLR as an independent risk factor for the OS (Table 2). In the Kaplan-Meier survival analysis, NLR increase predicted a poorer prognosis as compared to NLR decrease (median OS, 30 months vs. 47 months, respectively; p=0.005; Fig 1). Relationships between preoperative biliary drainage and the values of the systemic inflammatory markers 6 The relationships between the presence/absence of preoperative biliary drainage and the values of the systemic inflammatory markers, including the NLR, PLR and GPS, are shown in Table 3. Increases of the NLR, PLR and GPS were significantly related to the preoperative use of biliary drainage. Relationships between the direction of change of the NLR and clinicopathological variables The clinicopathological variables in patients grouped by the direction of change of the NLR are shown in Table 4. There were no significant differences in either the clinical variables or the tumor characteristics between groups stratified according to the direction of change (increase or decrease) of the NLR. Discussion The first causal link between inflammation and cancer was reported by Rudolf Virchow in 1863, who described the presence of leukocytes in neoplastic tissues [12, 19]. Tumors can not only develop under the stimulation of inflammation, but can also induce systemic and local inflammatory responses that may provide a favorable microenvironment for tumor invasion and metastasis [4, 20]. The systemic inflammatory response is associated with the release of pro-inflammatory cytokines such as interleukin (IL)-6, and growth factors, resulting in tumor growth and metastasis [3, 7, 13, 20]. Kusumanto et al. [21] reported that circulating neutrophils contain and secrete the major portion of 7 the circulating vascular endothelial growth factor (VEGF). VEGF is a pro-angiogenic factor that is known to promote tumor angiogenesis, and may play an integral role in tumor growth and progression [14, 16, 20, 22, 23]. Lymphocytopenia is an indicator of immunosuppression at both the local and systemic levels [13, 14]. Thrombocytosis is related to the stimulation of megakaryocytes by pro- inflammatory mediators such as IL-1 and IL-6 [7, 13]. CRP, white is an acute-phase protein produced by the hepatocytes, is related to the systemic inflammation, and hypoalbuminemia, an indicator of malnutrition, is known to be related to impaired host immunity [13, 20]. Thus, some studies have indicated the existence of associations between the values of several inflammatory markers, such as the NLR, PLR and GPS, calculated from variables reflecting systemic inflammation, and the prognosis in cancer patients, including those with pancreatic cancer [4- 11]. In this study, the NLR, PLR and GPS were not identified as significant prognostic factors in pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy. This could be thought to be attributable to the use of preoperative biliary drainage. Lewis et al. [6] pointed out in their systematic review that many studies were poorly reported inclusion of patients who had preoperative biliary drainage. Shirai et al. [7] reported that an increase of the PLR was associated with the presence of preoperative biliary drainage. In this analysis, we excluded cases with evidence of infection. Notwithstanding, the values of each of the systemic inflammatory markers were significantly related to the preoperative use of biliary drainage. Thus, these systemic inflammatory 8 markers were probably not identified as prognostic factors in this study as they may more strongly reflect the potential infectious status caused by preoperative biliary drainage. In this study, we determined the change of the NLR after one cycle of adjuvant chemotherapy as compared to the value recorded prior to the start of the therapy, and demonstrated that a decrease of the NLR after adjuvant chemotherapy was associated with a median OS of 47 months whereas an increase was associated with a median OS of 30 months (P = 0.005). Thus, the direction of change of the NLR after the start of chemotherapy was identified as an independent prognostic factor for OS in pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy. Resection followed by adjuvant chemotherapy represents the current gold standard therapy for resected pancreatic cancer. Therefore, it is very important to identify the subgroup of patients who will benefit most from adjuvant chemotherapy in the multimodality therapy [2, 8]. The direction of change of the NLR, which can be easily measured, might be useful to predict the efficacy of adjuvant chemotherapy in resected pancreatic cancer patients. Luo et al. [2] reported that the postchemotherapy direction of change of the NLR could be used to predict the response to chemotherapy in patients with advanced pancreatic cancer undergoing chemotherapy. To the best of our knowledge, this is the first report describing the existence of a correlation between the OS and post-treatment direction of change of the NLR in pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy. 9 Until now, most identified prognostic factors depend on the pathologic characteristics of the resected tumor specimen determined after surgery [14, 20]. Meanwhile, some studies have reported the existence of correlations between the values of systemic inflammatory marker, including the NLR, and the pathological variables. For example, a correlations have been reported between the NLR and the tumor differentiation grade, advanced disease stage, and positive nodal status [14, 16]. On the other hand, Bhatti et al [3] reported that while the NLR showed no significant association with any of the pathological factors, it was a significant independent prognostic factor. In this study also, the NLR change was identified as a significant independent prognostic factor, but was not associated with any clinicopathological variables. Therefore, the association between the direction of change of the NLR and the prognosis cannot be solely explained by the pathological variables. Recent studies have identified myeloid-derived suppressor cells (MDSCs), which are potent suppressors of tumor immunity, and the negative regulatory programmed death-1/programmed death- 1 ligand (PD-1/PD-L) pathway in T-cell activation [24, 25]. Ohigashi et al. [24] reported that the PD- L status was an independent prognostic factor in patients with esophageal cancer. The significance of the PD-L status in other cancers and the effects of immunotherapy targeting the PD-L status have been investigated. Some studies have suggested that the percentage of MDSCs in peripheral circulating blood is increased in various types of cancers, including pancreatic cancer, as compared to that in normal volunteers, and that the MDSCs contribute to chemoresistance of tumors [25, 26]. Ohki et al. 10 [25] suggested that the depletion of MDSCs could be a strong tool for adjuvant therapy if chemotherapy successfully decreases the count of MDSCs. Therapy targeted at the depletion of MDSCs might represent a new approach for cancer immunotherapy [27, 28]. The PD-L status and MDSCs, associated with immune evasion and suppression, are closely related to tumor growth and metastasis. A recent study reported a significant association between the count of MDSCs and the NLR in patients with gastric and colorectal cancer [25]. Although the post-treatment direction of change of the NLR was identified as an independent prognostic factor in this study, it was not associated with either the clinical variables or the tumor characteristics. Thus, this study might suggest that the direction of change of the NLR following treatment might reflect tumor immune evasion and suppression, reflected by the PD-L status and count of MDSCs. Adjuvant chemotherapy inhibits the PD-L pathway and activity of the MDSCs. As a result, a decrease of the NLR after adjuvant chemotherapy was associated with a better prognosis than an increase of the NLR after adjuvant chemotherapy Only few reports of investigation of the prognostic significance of systemic inflammatory marker values in the adjuvant chemotherapy setting in pancreatic cancer patients have been published [8, 29]. The direction of change of the NLR after adjuvant chemotherapy may help in predicting the effect of chemotherapy, including immunotherapy, in pancreatic cancer patients. The sample size in our study was relatively large as compared to that in previously reported studies. 11 However, the major limitation of this study was that it was retrospective in nature and was conducted at a single institution. Although our findings were of interest, their clinical relevance is not yet completely understood and further research is required. In conclusion, systemic inflammatory marker values are influenced by the use of preoperative biliary drainage, caution should be exercised while interpreting the significance of changes in the values of systemic inflammatory markers. 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