Introduction

The detection rate of pancreatic cysts has increased dramatically owing to the universal use of cross-sectional imaging modalities1,2. Pancreatic cystic neoplasms (PCNs)account for approximately 10%–15% of all pancreatic cystic lesions1,3 and approximately 1% of all pancreatic neoplasms3.PCNs include three distinct common tumor types: serous cystic neoplasm (SCN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN)4,5.IPMN and MCN are believed to potentially lead to pancreatic ductal adenocarcinoma, whereas SCN is almost always benign4,6,7.

Some PCNs undergo malignant transformation, and detection thus provides an opportunity to surgically cure or prevent pancreatic adenocarcinoma8. In current clinical practice, evaluation of the benign or malignant status of PCNs remains a major challenge. Surgery is recommended for all suitable patients with suspected PCNs9,10. However, it is important to consider that pancreatic surgery is risky, and the possibility of major postsurgical complications (as well as of long-term impairment of pancreatic function) is nonnegligible11,12. The risk of over-treatment (unnecessary pancreatectomy) should be balanced carefully with the risk of under-treatment (missing the opportunity to cure a potentially curable malignant or premalignant lesion)4. The differentiation of a potentially malignant cystic neoplasm from other benign neoplasms prior to surgery plays an important role in treatment planning13,14. Use of a combined diagnostic method is recommended not only for preoperative diagnosis, to reduce the performance of unnecessary surgery in patients with observable progress, but also to prevent surgical delay when appropriate9.

Unfortunately, based on current guidelines, diagnosis and management of PCNs is a clinical challenge15. Preoperative diagnosis of pancreatic cysts is largely reliant on radiographic pathologists. Tumors were classified as benign or malignant according to the American Joint Committee on Cancer(AJCC), 7th edition.

Development of the combined criterion

The receiver operating characteristic (ROC) curve and area under the ROC curve were applied to determine the best cutoff values for baseline NLR. We defined the presence of any two or more of the three predictive factors, including abnormal serum CA19-9 level, NLR＞cut-off value, and enhanced solid component on CT imaging, as meeting the criterion for malignancy.

从表2得知，学生的学习计划方面已经有了明显提高。但是，学生中的大部分没有及时监控学习过程、调节学习方法，在英语学习中不能熟练使用监控策略和调节策略。

Statistical analysis

For continuous variables, descriptive statistics were used and were reported as mean ± standard deviation (SD) or as median with range. Categorical variables were described using frequency distributions. An independent sample t-test was calculated to detect differences in the means of continuous variables. Chi-square and Spearman rank correlation coefficient testing were used for qualitative variables, and one-way analysis of variance (ANOVA) was applied to detect differences among several groups. All variables with statistically significant malignant predictive value in univariate analysis were selected for further investigation in the multivariate analyses. All statistical analysis was performed using the SPSS software (version 18.0; SPSS Inc., Armonk, NY, USA). P values were two-tailed and regarded as significant when less than 0.05.

Various investigations of NLR have been performed in various types of cancer, considering its role in the prediction of cancer development29,45. A strong connection between neutrophil infiltration and malignant progression has been described by inflammatory mediators released by peripheral blood cells, which play a vital role in the intersection between neoplastic and inflammatory cells46. Recently, it was reported that tumorigenesis in the pancreas correlates with distinct intra- and peri-tumoral inflammation47. Thus, despite its non-specificity, increased NLR might be indicative of increased inflammatory activation in PCN-derived malignancies. The present study demonstrated that NLR is significantly higher in patients diagnosed with malignant PCNs than in those with benign lesions. As there was a remarkable difference in NLR value between healthy volunteers and patients with malignant PCNs, NLR might be important for monitoring malignant progression of PCNs.Intriguingly, in our study, we found that the cut-off value of NLR ＞1.976 was an independent predictor for the malignant potential of PCNs. Other studies selected different cut-off values of NLR48,49, but these findings all indicate that high NLR is a supportive predictor of malignancy in PCNs.

Results

Characteristics of study subjects

Owing to the morphological overlap in imaging, and poor inter-observer consensus in relation to the standards between benign and malignant PCNs, CT images allow correct characterization of only 25%–60% of cystic pancreatic masses40. Numerous researchers have reported that the presence of solid component inside the cyst on imaging is a significant predictor of malignancy40. In the present study also, the most significant radiological finding correlated with malignancy was the presence of enhanced solid component.Moreover, the presence of enhanced solid component was found to be an independent predictor in multivariate analysis.

Correlation between clinical characteristics and PCN malignancy

Serous cystadenomas, which are often located in the body or tail of the pancreas, occur most commonly in middle-aged women. In contrast, IPMN occurs more frequently in the pancreatic head in elderly male patients, and mucinous cystadenomas occur mostly in elderly females34,36. In our results, sex could not be considered a predictor of malignant PCN. Patients with benign MCN have a median age of 50 years, whereas patients with mucinous cyst adenocarcinoma have a median age of 65 years3. Other studies reported that patients with malignant cysts were older than patients with benign cysts, with statistical significance16,37. This observation is consistent with our findings that age is correlated with malignant cystic pancreatic neoplasms.

Representative pathology and images of both benign and malignant lesions are shown in Figure 1. Patients with malignant PCNs had a higher probability of exhibiting enhanced solid components on CT images (P＜0.001)(Table 1). It is unsurprising that the presence of an enhanced solid component is strongly associated with malignant PCNs.

To determine whether NLR prior to surgery was predictive of malignant potential, we compared the preoperative NLR in 124 patients with benign PCNs with that in 41 patients with malignant PCNs. The NLR of patients with benign PCNs (1.87±0.84) was significantly lower than that of patients with malignant PCNs (2.81±2.14, P=0.009).Furthermore, we compared peripheral blood NLR in patients with benign PCNs, malignant PCNs, PNET, PDAC, and IgG4-related sclerosing pancreatitis, with that in healthy controls (Figure 2). The NLR in patients with malignant PCNs was similar to that in patients with PDAC (P=0.640),and was significantly higher than that in patients diagnosed with PNET (1.90 ± 0.69, P=0.013) or in healthy donors (1.40 ±0.48; P＜0.001). NLR in patients with malignant PCNs and PDAC was higher than that in healthy volunteers, indicating that the increase in NLR might be caused by tumor microenvironment.

Independent factors predicting malignancy in PCNs

The optimal cut-off value of NLR for predicting malignant PCNs was 1.976 (AUC=0.673, Figure 3). Patients were divided into a low NLR group (NLR≤1.976; n=96) and a highNLR group (NLR ＞1.976; n=69). To evaluate the utility of NLR prior to surgery in identifying patients with malignancy,logistic regression analysis was performed with clinical parameters including NLR (Table 2). Univariate analysis showed that high NLR (＞1.976), older age (＞56 years), high CA19-9 (≥39 U/mL), high CEA (≥5 ng/dL), high CA242 (≥12 U/mL), presence of enhanced solid component, and tumor location in the body or tail of pancreas were all significantly associated with malignancy. Multivariate analysis revealed that high CA19-9 (≥39 U/mL), presence of enhanced solid component, and high NLR were independent predictors of PCN malignancy.

Table 1 Background characteristics of patients with PCNs

aStudent’s t-test for age and NLR distributions between benign and the malignant group; and two-sided χ2 test for other selected variables.

Clinicopathological factors Benign group (n=124) Malignant group (n=41) χ2 P Age, years 55.00±12.23 61.41±8.95 3.092 0.002 NLR 1.87±0.84 2.81±2.14 2.738 0.009 Sex (male/female) 44/80 21/20 3.196 0.074 Age, years≤56 58 13 2.853 0.091＞56 66 28 CA19-9 (U/mL)＜39 112 15 50.194 ＜0.001≥39 12 26 CEA (ug/L)＜5 113 31 6.681 0.010≥5 11 10 CA242 (U/mL)＜12 95 17 17.460 ＜0.001≥12 29 24 Enhanced solid component Absence 88 10 27.717 ＜0.001 Presence 36 31 Cyst diameter (mm)＜30 53 15 0.482 0.487≥30 71 26 Symptom Absence 59 10 6.811 0.009 Presence 65 31 Tumor location Head/neck 56 29 8.066 0.005 Body/tail 68 12

Clinical utility of NLR and the new combined criterion

Figure 1 (A) A 69-year-old asymptomatic woman with pancreatic body-tail cyst incidentally found by routine examination. (1) Computed tomography (CT) scan shows 8 cm cyst at body-tail of pancreas. (2) Axial contrast-enhanced CT image in portal venous phase demonstrates a large nonenhancing mass in pancreas (arrow). (3) Serous cystic neoplasm (SCN) confirmed by pathology (IHC staining, 20 x). (B) A 48-year-old woman with upper abdominal pain. (1) Computed tomography (CT) scan shows 7 cm cyst at body-tail of pancreas. (2) Axial contrast-enhanced CT image in portal venous phase demonstrates a large enhancing mass in pancreas (arrow). (3) Invasive mucinous cystic neoplasm (MCN) confirmed by pathology (IHC staining, 20 x).

Figure 2 Distribution of NLR in 603 patients with various types of pancreatic disease is shown. NLR values are compared among these groups. Healthy volunteers (n=330), PDAC: pancreatic ductal adenocarcinoma (n=49), PNET: pancreatic neuroendocrine tumor(n=44), IgG4: IgG4-related sclerosing pancreatitis (n=15), benign PCNs in the study (n=124), malignant PCNs in the study (n=41).＊P＜0.05, ＊＊P＜0.01.

Medical consensus suggests 3 cm as the cut-off value for resection of asymptomatic lesions8. On the other hand, large numbers of studies have reported that cyst size had little correlation with pathological malignant traits35. Sarr et al.38 reported no difference in the mean size between benign mucinous cystadenoma and mucinous cystadenocarcinoma.Lee et al.39 found that 19% (31/166) of cystic pancreatic tumors ＜3 cm proved to be malignant. In the present study,lesion size was also not predictive of malignant cysts.However, we found that tumor location was a predictive factor of malignant PCNs. Lesions located in the body or tail of the pancreas were more likely to be malignant.

实验试样为Al-Si系铝合金，其由各原料熔炼制得．由于某些合金化元素的纯金属熔点很高，难以用于熔制铝合金，因此为避免上述问题，实验中熔炼制备试样的原料采用的是纯铝、纯锌及Al-33%Si，Al-50%Cu，Al-10%Mn，Al-10%Mg，Al-10%Fe，Al-10%Ni和Al-10%La等合金元素的中间合金．设计七组实验试样，采用完全相同的处理方式制备不同成分的合金试件，不同试样的组成成分列于表1．

Figure 3 Optimal NLR value for predicting malignant PCNs.Receiver operating characteristic (ROC) curve analysis for determining NLR cut-off value predictive of malignant PCNs is shown. Curved line shows ROC curve. AUC: area under the curve,COV: cut-off value.

Table 2 Univariate and multivariate analysis for predicting malignancy in PCNs

Factors Univariate analysis Multivariate analysis Odds ratio 95 % CI P Odds ratio 95 % CI P Age (＞ 56 years) 1.893 0.897–3.993 0.094 Sex (male/female) 0.524 0.256–1.070 0.076 NLR ＞1.976 4.360 2.046–9.293 ＜0.001 4.892 1.735–13.792 0.003 CA19–9 ≥39 U/mL 16.178 6.772–38.645 ＜0.001 13.527 3.673–49.822 ＜0.001 CEA ≥5 ng/dL 3.314 1.289–8.518 0.013 1.048 0.247–4.441 0.950 CA242 ≥12 U/Ml 4.625 2.190–9.767 ＜0.001 1.176 0.343–4.026 0.796 Enhanced solid component 7.578 3.366–17.059 ＜0.001 6.629 2.323–18.917 ＜0.001 Cyst diameter ＞30 mm 1.294 0.625–2.680 0.488 Symptom 2.814 1.270–6.232 0.011 2.139 0.691–6.626 0.187 Tumor location 0.341 0.159–0.729 0.006 0.657 0.225–1.916 0.442

Figure 4 High NLR level is associated with the presence of malignant PCNs. Distributions of NLR level and serum CA19-9 level, presence of enhanced solid component, and presence of malignant lesions in patients with PCNs (n=165) are shown. Each bar chart shows the patient's NLR value, and lower heat map shows if patient meets the criterion. Red arrow shows the high NLR group (＞1.976).

Table 3 The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and accuracy for predicting PCNs malignancy of NLR, CA19-9, presence of enhanced solid component and combined criterion are all shown

aMeeting both of the elements including serum CA19-9 ≥39 U/mL and the presence of enhanced solid component in CT imaging.

Factors Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%)NLR＞1.976 40.6 86.5 68.3 66.9 67.3 CA19-9≥39 U/mL 68.4 88.2 63.4 90.3 83.6 Presence of enhanced solid component 46.3 89.8 75.6 71.0 72.1 CA19-9 and enhanced solid component 83.3 85.1 48.8 96.8 84.8 Combined criterion 68.8 93.2 80.5 87.9 86.1

Discussion

PCNs are now more frequently discovered with the increased use of abdominal CT imaging33. Some of these neoplasms undergo malignant transformation8,34. Therefore,considering the current efficacy of pancreatic resection, it is not surprising that the number of operations for PCNs has increased. Pancreatic resection can remove symptomatic,malignant, or potentially malignant lesions. However, some cystic lesions are benign or slow growing, and their potential for malignant transformation remains unclear33. Recent studies have shown that only one-fifth of the resected asymptomatic pancreatic cysts are malignant35. Surgeons require a rapid and accurate assessment of the risk benefit ratio of observation versus resection of these neoplasms in individual patients.

In clinical practice, CA19-9 and CEA are two of the important biomarkers for patients with pancreatic malignant diseases41. Serum CA19-9 level is elevated in more than three quarters of patients with pancreatic ductal adenocarcinoma42.These biomarkers were found to be correlated with the presence of malignancy. An increased level of CA19-9 was found to be specifically correlated with malignant PCNs.Thus, CA19-9 is considered to be a vital test for all patients, a finding consistent with the results of other series8. However,although the specificity of serum CA19-9 is high, its sensitivity has been shown to be very low42. Some researchers have suggested that endoscopic ultrasound with fine-needle aspiration (EUS-FNA) and cystic fluid analysis hold promise in identifying lesions with malignant potential43. EUS is not always accessible, however, particularly in rural areas where the equipment for distinguishing malignant lesions from benign PCNs is not available44. Limitations to the access of EUS indicate that clinicians must rely on other noninvasive techniques to assess the risk of PCN.

According to pathology results, the patients were divided into benign and malignant groups. Sex could not be considered a predictor of malignancy in the patients with PCNs. Tumor location between body or tail of the pancreas and older age were significantly associated with malignancy (P=0.005,P=0.002, respectively) (Table 1). Symptoms at admission were recorded more often in the malignant group (31/41;75.6%) (P=0.009). Preoperative serum CA19-9, CA242, and CEA levels were closely associated with PCN malignancy(P＜0.001, P＜0.001, and P=0.010, respectively) (Table 1).

Next, we aimed to identify whether NLR could be a supportive index to predict malignancy of PCNs when combined with other conventional indicators. The distribution of NLR value, serum CA19-9 level, presence of enhanced solid component, and the presence of PCN malignancy is shown in Figure 4. The sensitivity, specificity,positive predictive value (PPV), and negative predictive value(NPV) for predicting PCN malignancy were evaluated with the combined criterion of NLR＞1.976, abnormal serum CA19-9 level, and presence of enhanced solid component.The sensitivity, specificity, PPV, NPV, and accuracy of the new diagnostic criterion for predicting PCN malignancy are shown in Table 3, in comparison with each conventional indicator of PCN malignancy. Furthermore, the sensitivity,specificity, PPV, and NPV predicted by the new criterion were 68.8%, 93.2%, 80.5%, and 87.9%, respectively. The new criterion demonstrated both a high PPV of 80.5% and a high NPV of 87.9%. Thus, a higher accuracy (86.1%) in identifying malignancy could be obtained with the new diagnostic criterion.

Table 1 shows the clinical characteristics of 165 patients with PCNs. Among these patients, 65 were men and 100 were women, with a mean age of 56.59 years (range, 20–81).Regarding tumor types, 29 patients had pancreatic IPMN, 67 had SCN, and 69 had MCN. While 124 cysts were identified as benign, 41 were malignant. Sixty-nine patients were asymptomatic, and 96 patients experienced one or more symptoms including abdominal pain/discomfort, vomiting,jaundice, weight loss, or abdominal mass. The mean diameter of PCNs was 4.60±2.65 cm (range, 1.2–16 cm). Regarding location, 51.5% (85) of PCNs were located in the head or neck of the pancreas, and 48.5% (80) were located in the body or tail. The mean NLR in all patients with PCN was 2.10±1.34. Serum CA19-9, CEA, and CA242 were measured in all patients. The ratios of normal to abnormal were 127/38,112/53, and 144/21 for CA19-9, CEA, and CA242,respectively. An enhanced solid component inside the cyst was observed in 77 patients (46.7%) on CT imaging.

众人兴奋起来。矿区秧歌会，从解放初到现在，一直很有名气。可他们肇下那么大事端，惹出那么大祸，还有心庆贺。何良诸觉得不可思议。

通过合作学习的方式，学生能够更好地掌握语文知识的学习，并促进其积极性的提升，进而激发小学生对该课文学习的乐趣，更好地解决其在学习过程中存在的问题，实现学生合作能力的提升。通过运用这种学习方式，师生与生生之间的情感都会得到升华，学习效率也被大大提升。由于社会各因素所产生的影响，导致很多学生与人交流时的难度不断增大，更加以自我为中心。通过合作学习的方式，使同学之间的交流更加密切，学生心理与人格等都会得到完善，进而实现快速成长。

依靠科技进步提升国家整体竞争力是新时期我国重要发展战略之一，要实现科技进步这一战略目标，必须要依托企业技术的进步。但当前，我国很多企业仍然缺乏核心技术，一些关键技术还无法做到自给。针对这种现状，必须要制定能够激发企业技术创新动力和活力的财税激励政策，通过财政补贴支持和税收优惠，为企业提供强有力的支撑，逐步提升我国企业的技术创新能力，实现科技强国的战略目标。

The conventional guidelines for the diagnosis of malignancy of PCNs were unsatisfactory and complex, owing to the variety of predictors and their ambiguity. Preoperative prediction of malignancy often depends on the surgeon’s experience or other important factors that are difficult to clearly ascertain and have low PPV and NPV50. The new combined criterion is a quantitative standard that is more accurate, practical, and convenient for all surgeons.Therefore, we recommend the diagnosis of malignancy of PCNs on the basis of CA19-9, NLR, and CT imaging.

In conclusion, we defined a new combined criterion to predict malignancy in patients with PCNs. The combined accuracy for predicting malignant PCNs was superior to that of any one of the abovementioned three standards. This criterion is superior to current practice in the identification of patients with malignant lesions in PCNs. It is important to distinguish benign from malignant lesions to select individuals who would benefit from early surgery.

中国禅宗创于唐朝，而日本禅宗则是在中国禅宗传入后，与本土文化结合后形成，从时间来说，形成于中国宋元时期。

Conflict of interest statement

No potential conflicts of interest are disclosed.

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