The preoperative HELPP score can be used as a prognostic assessment tool for resectable pancreatic cancer patients, and may be applicable to patients in China as well

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, characterized by a low surgical resection rate, and a poor prognosis. According to a report from the American Cancer Society (ACS), the incidence of pancreatic cancer is increasing by approximately 1% each year, and it has the worst overall prognosis of all malignant tumors (1). It is the third leading cause of cancer-related death, and has a dismal 5-year survival rate of only 13% (1). Surgical resection is currently the only curative treatment available for PDAC, and its postoperative outcomes remain unsatisfactory.

Based on imaging findings, pancreatic cancer is categorized into three groups: resectable, borderline resectable, and unresectable tumors. Neoadjuvant therapy has been shown to reduce tumor size, increase the curative resection (R0 resection) rate, and lower tumor stage, ultimately improving the prognosis of patients with borderline resectable pancreatic cancer (2-5). There is a growing consensus regarding the prioritization of neoadjuvant therapy for these patients (2-5). However, controversy continues as to whether those with resectable pancreatic cancer can also benefit from this treatment (5,6).

The National Comprehensive Cancer Network guidelines recommend neoadjuvant therapy for patients with high-risk factors, but they do not provide clear indications (7). Existing staging systems, such as the 8^th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification system, along with other prognosis-related indicators, including tumor size, differentiation, and margin status, require invasive procedures to be performed to obtain pathological results to evaluate prognosis (8). Further, patients at the same TNM stage may exhibit significant biological variations, which limit the accuracy of TNM classification (9).

Carbohydrate antigen 19-9 (CA19-9) is commonly used in diagnostic and prognostic assessments; however, approximately 10% of patients are Lewis antigen-negative and do not express CA19-9 (10). Moreover, CA19-9 levels can be elevated in other medical conditions, leading to potential false negatives and false positives. Therefore, a novel preoperative assessment tool that can effectively predict postoperative prognosis in pancreatic cancer patients urgently needs to be developed, which in turn would enable the development of more tailored treatment plans before surgery.

Studies have shown that the inflammatory response is closely related to the occurrence and development of tumors (11,12). Based on this, peripheral blood inflammatory indicators have been found to be related to pancreatic cancer prognosis, and some prognostic indicators, such as the neutrophil-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and Glasgow prognostic score (GPS), have been developed. The NLR is a peripheral blood indicator with prognostic value for a variety of malignant tumors (13,14), but there are some differences in related research results (15). The SII is a novel inflammatory marker that can comprehensively reflect the balance of inflammation and immunity by considering the counts of neutrophils, lymphocytes, and platelets. Studies have shown that the SII plays an important role in the prognosis of some digestive tract tumors, including pancreatic cancer (16-21). The GPS combines C-reactive protein (CRP) and albumin to reflect both nutritional and inflammatory status (22) (Table S1), and has been shown to have potential value in the assessment of prognosis in patients with pancreatic cancer (23-25).

The Heidelberg prognostic pancreatic cancer (HELPP) score is a preoperative pancreatic cancer prognosis assessment tool published in March 2021 by a team at Heidelberg University Hospital in Germany (26) (Table S2). The HELPP score can provide a preoperative prognostic assessment independent of the pathological stage. In China, to date, only the team of Nanjing Drum Tower Hospital has conducted a small-sample, single-center retrospective study on the HELPP score (27). Thus, more studies need to be conducted to confirm the effectiveness of the HELPP score.

Objective

This study performed a retrospective analysis to investigate the correlation between the preoperative HELPP score, GPS, SII, and NLR, and the postoperative prognosis of resectable pancreatic cancer patients, these indicators were used to stratify patients preoperatively to identify those with poor prognosis for preoperative adjuvant therapy, ultimately aiming to formulate a more appropriate preoperative treatment plan for those with resectable pancreatic cancer. We present this article in accordance with the TRIPOD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-132/rc).

Methods

This study employed a retrospective cohort study aimed at analyzing the effectiveness of preoperative prognostic scoring indicators in patients with pancreatic cancer who underwent radical resection. The sample size of this study was 61 patients, consisting of all individuals who met the criteria and underwent radical surgery for pancreatic cancer at Zhongshan Hospital of Xiamen University from February 2015 to February 2022. As this is an exploratory study, based on previous similar research and the expected effect size, the sample size is sufficient for preliminary statistical analyses. The inclusion criteria: (I) have undergone radical resection for pancreatic cancer; (II) have a postoperative pathologic diagnosis of PDAC; and (III) have complete clinical, follow-up, and pathological data. The exclusion criteria: (I) had infectious diseases or hematological diseases leading to abnormal inflammatory indicators or platelet counts before surgery; (II) had died from serious complications within 1 month of surgery; and/or (III) had received neoadjuvant therapy prior to surgery (this criterion was included to ensure that patients with borderline resectable pancreatic cancer were excluded from the study).

Clinicopathological data were collected within 2 weeks before surgery, including gender, age, American Society of Anesthesiologists (ASA) classification, CA19-9, carcinoembryonic antigen (CEA), CRP, albumin, neutrophil count, lymphocyte count, platelet count, presence of diabetes, adjuvant therapy received post-surgery, surgical margins, tumor size, tumor location, degree of differentiation, presence of vascular and nerve invasion, and staging (TNM) according to the 8^th edition of the AJCC. Tumor resection margin status (R) was classified as R0 (no tumor at the margin) or R1 (tumor present within 1 mm of the margin).

Patient follow-up was conducted via telephone interviews, outpatient visits, and medical record reviews. The follow-up period started from the date of surgery and ended on February 20, 2024. Overall survival (OS), defined as the time from surgery to death or last follow-up, was the primary endpoint. Details of postoperative adjuvant therapy were also recorded for comprehensive prognostic analysis. Patients were followed up by telephone, and by review of cases or outpatient medical records. The follow-up included the collection of postoperative adjuvant therapy and survival data. The follow-up start date was the date of surgery, and the follow-up end date was up to February 20, 2024. OS was defined as the time from the date of surgery to the last follow-up or the patient’s death.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of Zhongshan Hospital of Xiamen University (No. 2025-076) and individual consent for this retrospective analysis was waived.

Statistical analysis

Plot time-dependent receiver operating characteristic (ROC) curves and Youden’s index were used to determine the optimal cut-off values for the NLR, the SII, and other quantitative data. Stratified pairwise comparative analyses were performed using the Kaplan-Meier method of plotting survival curves, and the log-rank test was used to further categorize and group patients based on HELPP scores. In our survival analyses, we performed both univariate and multivariate Cox proportional hazards regression models to adjust for potential confounding effects of baseline clinical covariates. Univariate and multivariate survival analyses using the Kaplan-Meier method and the Cox proportional-hazards model were conducted to explore the relationship between the HELPP score, GPS, SII, NLR, and postoperative survival of patients with pancreatic cancer, and the hazard ratios (HRs) were calculated. For scoring tools related to postoperative survival, between-group comparisons of clinicopathologic data were performed using the Chi-squared test for patients in each scoring method subgroup. Predictive accuracy was assessed by plotting ROC curves and comparing the areas under the ROC curves (AUCs). The statistical analyses were performed using R statistical software (version 4.2.0) and SPSS 26.0. All statistical tests in our study, including hypothesis testing for survival differences and covariate associations, were two-sided. A P value <0.05 was considered statistically significant. For evaluating the predictive performance of the prognostic scores, an AUC of ≥0.7 is considered to have good predictive ability.

Results

Clinicopathological characteristics of the patients

Based on the inclusion criteria, 89 pancreatic cancer patients were initially included in the study. After excluding patients with incomplete data (21 patients) and those who received neoadjuvant therapy before surgery (13 patients), 61 patients (57.4% male) were ultimately included in this analysis. Of the patients, as of February 20, 2024, the number of surviving pancreatic cancer patients is 33, and the number of deaths is 28. Of the patients, 18 (29.5%) were aged ≥65 years and 43 (70.5%) were aged <65 years. Additionally, 47 patients (77.0%) had tumors located in the head of the pancreas, and 14 (23.0%) had tumors located in the tail/body. Of the patients, 15 (24.6%) had poor tumor differentiation, and 46 (75.4%) had medium-high tumor differentiation. The clinicopathological data of the patients are presented in Table 1.

Statistics for various prognostic scores

The optimal cut-off values for the SII and NLR were 675.51 (Youden’s index: 0.406) and 2.53 (Youden’s index: 0.379), respectively. Further, the optimal cut-off values for age, platelets, albumin, CA19-9, CEA, and CRP were 65 (Youden’s index: 0.247), 261 (Youden’s index: 0.320), 38.43 (Youden’s index: 0.133), 69.27 (Youden’s index: 0.532), 1.48 (Youden’s index: 0.491), and 1.77 (Youden’s index: 0.359), respectively. As Table 2 shows, based on the defined cut-off values, 32 patients had a high SII (52.5%) and 29 had a low SII (47.5%), and 28 patients (45.9%) had a high NLR and 33 (54.1%) had a low NLR. Eleven (18.0%), 12 (19.7%), 8 (13.1%), 19 (31.1%), 8 (13.1%), and 3 (4.9%) patients had HELPP scores of 0, 1, 2, 3, 4, and 5 points, respectively. While 47 (77.0%), 13 (21.3%), and 1 (1.6%) patients had a GPS of 0, 1, and 2 points, respectively (Table 2).

Prognostic difference analysis and further grouping based on the HELPP score

The Kaplan-Meier survival curve was plotted (Figure 1), and the log-rank test was used to make pairwise comparisons of each HELPP score. The results revealed there were no statistically significant prognostic differences between the pancreatic cancer patients with HELPP scores of 1, 2, and 3 points (P=0.25, 0.40, and 0.90, respectively), and nor such statistically significant differences were found between the patients with HELPP scores of 4 and 5 (P=0.058) (Table 3). In the results of the external validation of the model by the team from Heidelberg University Hospital, no statistically significant difference was found in the survival analysis between the subgroups with HELPP scores of 0 and 1 points and the subgroups with HELPP scores of 2 and 3 points, but a statistically significant difference was found between the subgroups with HELPP scores of 4 and 5 points and the other subgroups (26). While in the study by the team from the Nanjing Drum Tower Hospital, the prognostic difference between the patients with HELPP scores of 1, 2, and 3 points was not statistically significant, nor was the prognostic difference between patients with HELPP scores of 4, 5, and 6 points (27). Combining the results from Zhongshan Hospital of Xiamen University with those of the two other teams, this study defined pancreatic cancer patients with HELPP scores ≤3 points as the low HELPP score group, and patients with HELPP scores >3 as the high HELPP score group. As a result, 50 patients were allocated to the low HELPP score group and 11 patients were allocated the high HELPP score group.

Figure 1 Kaplan-Meier curves for OS stratified by the HELPP score. OS, overall survival; HELPP, Heidelberg prognostic pancreatic cancer.

Univariate survival analysis of prognostic factors among patients with PDAC

The median postoperative OS times of the 61 patients with pancreatic cancer were 27 months (range, 3–69 months). Using the Kaplan-Meier method and log-rank test to perform the survival analysis, we found that the median OS times of the postoperative pancreatic cancer patients in the low HELPP score group and the high HELPP score group were 32 and 7 months, respectively, and the difference in the survival times between the two groups was statistically significant (P<0.001) (Figure 2A). The median OS times of the postoperative pancreatic cancer patients with a GPS of 0, 1, and 2 points were 32, 16, and 11 months, respectively, but the difference in the survival times between these groups was not statistically significant (P=0.18) (Figure 2B). The median OS times of the postoperative pancreatic cancer patients with a low SII and a high SII were 34 and 17 months, respectively, and the difference in the survival times between the two groups was statistically significant (P=0.009) (Figure 2C). The median OS times of the postoperative pancreatic cancer patients with a low NLR and a high NLR were 33 and 19.5 months, respectively, but the difference in the survival times between the two groups was not statistically significant (P=0.051) (Figure 2D).

Figure 2 Kaplan-Meier curves for OS stratified by the HELPP score (A), GPS (B), SII (C), and NLR (D). GPS, Glasgow prognostic score; HELPP, Heidelberg prognostic pancreatic cancer; NLR, neutrophil-lymphocyte ratio; OS, overall survival; SII, systemic immune-inflammation index.

The Cox proportional-hazards model was used for the univariate survival analysis of the data of the 61 patients, and we found that high CA19-9 (P=0.002), high CEA (P=0.004), high CRP (P=0.03), low tumor differentiation (P=0.001), a large tumor diameter (P=0.02), high SII (P=0.01), a high HELPP score (P<0.001), and a high ASA classification (P=0.002) were risk factors affecting the OS of patients with pancreatic cancer after surgery, and these factors were significantly associated with patient prognosis (Table 4).

Multivariate survival analysis of prognostic factors among patients with PDAC

The Cox proportional-hazards model was used for the multivariate survival analysis, and we found that CEA ≥1.48 µg/L (P=0.02), a tumor diameter >4 cm (P=0.02), and a HELPP score >3 points (P<0.001) were independent risk factors affecting the OS of PDAC patients after surgery. Patients in the high HELPP score group had a significantly higher risk of death than those in the low HELPP score group [HR =19.259; 95% confidence interval (CI): 5.448–68.077; P<0.001] (Table 5), but no significant association was found between the GPS, SII, and NLR and prognosis of PDAC patients after surgery (P>0.05) (Tables 4,5).

Comparison of the clinicopathologic characteristics between the two HELPP score groups

In this study, we found that the HELPP score was the only factor independently associated with the prognosis of pancreatic cancer patients postoperatively. We then used the Chi-squared test to compare the clinicopathological characteristics between the two groups of patients with low and high HELPP scores, and we found that there was no statistically significant difference between the two groups of patients in terms of gender, age, diabetes, degree of tumor differentiation, nerve invasion, vascular invasion, tumor location, tumor size, receiving or not receiving adjuvant therapy postoperatively, surgical margin, and TNM classification (P>0.05) (Table 6).

Comparison of the efficacy of each prognostic scoring method

ROC curves were used to analyze the accuracy of the four indexes (i.e., the HELPP score, GPS, SII, and NLR) in predicting survival outcomes. Figure 3A shows the effectiveness of the HELPP score in predicting 1-year survival, which had an AUC of 0.874 (P<0.001). Figure 3B shows the effectiveness of the HELPP score in predicting 2-year survival, which had an AUC of 0.696 (P=0.009) (Table 7). Thus, the HELPP score had good accuracy in predicting prognosis in the first year after surgery, and its accuracy in the first year was better than that in the second year.

Figure 3 ROC curves were generated to evaluate the prognostic predictive ability of the HELPP score, GPS, SII, and NLR at 1 year (A) and 2 years (B). GPS, Glasgow prognostic score; HELPP, Heidelberg prognostic pancreatic cancer; NLR, neutrophil-lymphocyte ratio; ROC, receiver operating characteristic; SII, systemic immune-inflammation index.

Figure 3A shows the effectiveness of the GPS, SII, and NLR in predicting 1-year survival, which had AUCs of 0.606 (P=0.25), 0.617 (P=0.20), and 0.599 (P=0.28), respectively. Figure 3B shows the effectiveness of the GPS, SII, and NLR in predicting 2-year survival, which had AUCs of 0.588 (P=0.24), 0.591 (P=0.22), and 0.571 (P=0.34), respectively (Table 7). None of these results were statistically significant, indicating that the GPS, SII, and NLR did not have good value in predicting the postoperative prognosis of pancreatic cancer patients.

Discussion

The team from Heidelberg University Hospital in Germany extracted the data of 1,197 patients who underwent surgery for resectable pancreatic cancer between July 2006 and June 2014 from their central database and laboratory information system for a retrospective analysis. Among these patients, 882 underwent radical surgical resection, while 312 only underwent exploratory surgery after discovering locally unresectable or metastatic disease during the procedure. The analysis revealed that six preoperative parameters (i.e., ASA classification, CA19-9, CEA, CRP, albumin, and platelet count) were independently associated with postoperative prognosis in pancreatic cancer patients. They use these six preoperative parameters to form the basis for the establishment of the HELPP score.

An external validation of the HELPP score was conducted in 266 pancreatic cancer patients who underwent surgery at Verona University Hospital from January 2013 to December 2016, and while no survival differences between the 0–1- and 2–3-point subgroups were found, significant survival differences in other subgroups were observed (26).

A preliminary retrospective analysis of the data of 35 patients who underwent radical surgical resection for pancreatic cancer at the Nanjing Drum Tower Hospital confirmed the applicability of the HELPP score for Chinese pancreatic cancer patients. The results revealed a statistically significant difference in prognosis between the patients with HELPP scores ≤3 points and those with scores >3 points, indicating that a high HELPP score suggests a worse prognosis (27).

Our study retrospectively analyzed the data of 61 pancreatic cancer patients who underwent radical resection at Zhongshan Hospital of Xiamen University from February 2015 to February 2022. The findings indicated that a HELPP score >3 points indicated a worse postoperative prognosis. In comparison to the study of the Nanjing Drum Tower Hospital team, our study had a larger sample size and also compared the performance of several popular models. Our results further confirm that the HELPP score could serve as a novel preoperative prognostic assessment tool, has a strong predictive ability, and is applicable to Chinese pancreatic cancer patients.

CA19-9 is the most commonly used tumor marker for clinical diagnosis and prognosis evaluation in pancreatic cancer patients. However, approximately 10% of patients are Lewis antigen-negative and do not express CA19-9 (10). Further, inflammatory conditions of the bile duct system or the presence of other malignancies may also elevate CA19-9 levels, potentially leading to false positives or negatives in prognosis assessments. Therefore, supplementary prognostic factors are essential for more accurate evaluations. Recent studies have linked ASA classification with the prognosis of patients across various malignancies, including pancreatic and gastric cancers, highlighting its importance in refining prognosis assessments for pancreatic cancer (28-30). CEA is another commonly used tumor marker for preoperative diagnosis and prognosis evaluation in pancreatic cancer, and has shown high sensitivity for gastrointestinal tumors (31,32). Platelets also play a significant role in tumor growth and metastasis. Tumor cells can induce platelet activation and aggregation, revealing an interaction between platelets and tumor cells (33,34). A study suggests that pre-treatment platelet counts may be related to prognosis in pancreatic cancer patients (35). Given the aggressive nature of pancreatic cancer, such patients often experience greater nutritional risks than those with other types of tumors. Poor nutritional status can weaken immune function and tolerance to anti-tumor treatments, increasing the risk of postoperative complications and leading to a poorer prognosis for cancer patients (36). Serum albumin, a non-acute phase protein synthesized by the liver with a long half-life, reflects the long-term nutritional status of patients, and serves as a common nutritional assessment indicator. Studies have shown that hypoalbuminemia is associated with a poor prognosis in pancreatic cancer patients (35,37,38).

Studies have reported a close relationship between inflammation and tumor development (11,12). Neutrophils play a pivotal role in inflammatory responses—they can secrete or promote the release of various inflammatory factors, induce damage to normal cells, and facilitate their transformation into tumor cells, significantly affecting tumor occurrence, progression, and metastasis (39,40). Neutrophils inhibit T cell activation and proliferation while recruiting regulatory T cells, enabling tumor cells to evade immune surveillance (41,42). Additionally, neutrophils can produce neutrophil extracellular traps that promote tumor progression and metastasis, resulting in localized sterile inflammation and tissue necrosis in the pancreas, which can adversely affect the prognosis of pancreatic cancer patients (43,44). Further, neutrophils may convert inactive tumor cells into actively proliferating tumor cells through interleukin (IL)-1 receptor antagonism, thereby influencing tumor progression (45). Concurrently, tumor cells release pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-α) to recruit neutrophils from circulation into the tumor microenvironment (43).

Lymphocytes provide the cellular basis for immune surveillance and monitoring, and play vital roles in destroying tumor cells, inhibiting tumor cell proliferation, and inducing apoptosis (46,47). A reduction in lymphocyte levels can negatively affect the prognosis of pancreatic cancer patients (48-50). Pro-inflammatory factors in the tumor microenvironment, such as TNF-α, IL-1, and IL-6, can stimulate the liver and other tissues to synthesize and release CRP. Elevated levels of CRP can promote the production of vascular endothelial growth factor and inhibit apoptosis in tumor cells, thereby facilitating tumor progression (51,52). Numerous studies have found a close correlation between CRP levels and the prognosis of pancreatic cancer patients, with high CRP levels indicating a poorer prognosis (53-55).

In this study, we also examined the GPS, NLR, and SII, all of which are established based on the aforementioned immune-inflammatory mechanisms. The clinical utility of the GPS in prognosticating various malignancies, such as non-small cell lung cancer, gastroesophageal cancer, and colorectal cancer, is well documented (56-58). Several studies have reported that a high GPS score is associated with a poor prognosis in postoperative pancreatic cancer patients (23-25). Some studies suggest that the NLR is significant for prognostic evaluation in pancreatic cancer patients (13,14,59), but other research indicates that the NLR may not predict survival rates in patients with resectable pancreatic cancer (15). The SII holds considerable value in predicting the prognosis of gastrointestinal tumors (17-19). Some studies have also shown that the preoperative SII has prognostic predictive value for pancreatic cancer. However, the optimal cut-off values of the SII in different studies are inconsistent (20,21). This study found that the GPS, NLR, and SII were not clearly correlated with the prognosis of postoperative pancreatic cancer patients.

The HELPP score addresses the potential for false positives or negatives when CA19-9 is used as a standalone prognostic marker. Compared to the SII and NLR, the HELPP score has clear scoring criteria, and thus is more straightforward to implement in clinical practice. Unlike TNM staging, the HELPP score does not require pathological parameters, which simplifies the preoperative assessment of pancreatic cancer patients. Further, the HELPP score redefines the critical values for albumin and CRP based on a large and unselected dataset, improving both its accuracy and sensitivity in prognostic predictions for pancreatic cancer.

As this study was a single-center retrospective analysis, the objectivity and accuracy of the conclusions might have been affected. Future well-designed multicenter prospective studies need to be conducted to further validate our findings.

Conclusions

A high preoperative HELPP score, high preoperative CEA, and a large tumor diameter were found to be independently associated with a poor prognosis in pancreatic cancer patients who underwent radical resection. The preoperative HELPP score can be used as a tool to assess the postoperative prognosis of patients with resectable pancreatic cancer, may be applicable to patients in China as well. The GPS, SII, and NLR were not found to be clearly associated with the postoperative prognosis of PDAC patients.

Acknowledgments

The authors would like to thank Fujian Medical University and Zhongshan Hospital of Xiamen University for providing us with access to their platform and resources.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-132/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-132/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-132/prf

Funding: This work was supported by the Xiamen Healthcare Guidance Program (to J.L., Q.L., H.L., Z.M., X.H., H.C., and Y.S.) (No. 3502Z20244ZD1080).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-132/coif). J.L., Q.L., H.L., Z.M., X.H., H.C., and Y.S. report that this work was supported by the Xiamen Healthcare Guidance Program (No. 3502Z20244ZD1080). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of Zhongshan Hospital of Xiamen University (No. 2025-076) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
2. Stoop TF, Theijse RT, Seelen LWF, et al. Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer. Nat Rev Gastroenterol Hepatol 2024;21:101-24. [Crossref] [PubMed]
3. Murphy JE, Wo JY, Ryan DP, et al. Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 2018;4:963-9. [Crossref] [PubMed]
4. Springfeld C, Ferrone CR, Katz MHG, et al. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol 2023;20:318-37. [Crossref] [PubMed]
5. van Dam JL, Janssen QP, Besselink MG, et al. Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. Eur J Cancer 2022;160:140-9. [Crossref] [PubMed]
6. Springfeld C, Neoptolemos JP. The role of neoadjuvant therapy for resectable pancreatic cancer remains uncertain. Nat Rev Clin Oncol 2022;19:285-6. [Crossref] [PubMed]
7. NCCN Guidelines Panel Disclosures. NCCN Clinical Practice Guidelines in Oncology-Pancreatic Adenocarcinoma (Version 2.2023). 2023. Available online: http://www.nccn.org/patients
8. Zhou B, Xu JW, Cheng YG, et al. Early detection of pancreatic cancer: Where are we now and where are we going? Int J Cancer 2017;141:231-41. [Crossref] [PubMed]
9. Xie T, Wang X, Li M, et al. Pancreatic ductal adenocarcinoma: a radiomics nomogram outperforms clinical model and TNM staging for survival estimation after curative resection. Eur Radiol 2020;30:2513-24. [Crossref] [PubMed]
10. Hess V, Glimelius B, Grawe P, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol 2008;9:132-8. [Crossref] [PubMed]
11. Hou J, Karin M, Sun B. Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age? Nat Rev Clin Oncol 2021;18:261-79. [Crossref] [PubMed]
12. Diakos CI, Charles KA, McMillan DC, et al. Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014;15:e493-503. [Crossref] [PubMed]
13. Novisedlakova M, Chovanec M, Ciernikova S, et al. Prognostic and predictive significance of inflammatory markers in patients with locally advanced unresectable and metastatic pancreatic cancer treated with first-line chemotherapy FOLFIRINOX or Gemcitabine/Nabpaclitaxel. Bratisl Lek Listy 2024;125:745-58. [Crossref] [PubMed]
14. García-Herrera JS, Muñoz-Montaño WR, López-Basave HN, et al. Combination of neutrophil-to-lymphocyte ratio and serum CA 19-9 as a prognostic factor in pancreatic cancer. J Gastrointest Oncol 2024;15:1805-19. [Crossref] [PubMed]
15. Chawla A, Huang TL, Ibrahim AM, et al. Pretherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio do not predict survival in resectable pancreatic cancer. HPB (Oxford) 2018;20:398-404. [Crossref] [PubMed]
16. Aziz MH, Sideras K, Aziz NA, et al. The Systemic-immune-inflammation Index Independently Predicts Survival and Recurrence in Resectable Pancreatic Cancer and its Prognostic Value Depends on Bilirubin Levels: A Retrospective Multicenter Cohort Study. Ann Surg 2019;270:139-46. [Crossref] [PubMed]
17. Chen L, Yan Y, Zhu L, 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;9:849-67. [Crossref] [PubMed]
18. Aoyama T, Maezawa Y, Hashimoto I, et al. The Systemic Immune-inflammation Index Is an Independent Prognostic Factor for Gastric Cancer Patients Who Receive Curative Treatment. In Vivo 2024;38:2001-8. [Crossref] [PubMed]
19. Esashi R, Aoyama T, Maezawa Y, et al. The Clinical Impact of the Systemic Immune-inflammation Index in Esophageal Cancer Patients Receiving Curative Treatment. Anticancer Res 2024;44:5035-41. [Crossref] [PubMed]
20. Lu JN, Zhou LS, Zhang S, et al. Performance of nutritional and inflammatory markers in patients with pancreatic cancer. World J Clin Oncol 2024;15:1021-32. [Crossref] [PubMed]
21. Murthy P, Zenati MS, Al Abbas AI, 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. [Crossref] [PubMed]
22. McMillan DC. An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer. Proc Nutr Soc 2008;67:257-62. [Crossref] [PubMed]
23. Kawakami T, Todaka A, Oshima K, et al. Biomarker analysis for patients with pancreatic cancer treated with nanoliposomal irinotecan plus 5-fluorouracil/leucovorin. BMC Cancer 2023;23:68. [Crossref] [PubMed]
24. Yu M, Li X, Chen M, et al. Prognostic potential of nutritional risk screening and assessment tools in predicting survival of patients with pancreatic neoplasms: a systematic review. Nutr J 2024;23:17. [Crossref] [PubMed]
25. Mohammed AA, Al-Zahrani O, Elsayed FM. The application of the Glasgow prognostic score to predict the survival in patients with metastatic pancreatic carcinoma. Indian J Palliat Care 2022;28:406-12. [Crossref] [PubMed]
26. Hank T, Hinz U, Reiner T, et al. A Pretreatment Prognostic Score to Stratify Survival in Pancreatic Cancer. Ann Surg 2022;276:e914-22. [Crossref] [PubMed]
27. Xie Y, Hang HX, Li G, et al. Prognostic value of Heidelberg Prognostic Pancreatic Cancer(HELPP)-score in patients with pancreatic cancer undergoing radical resection. Chinese Journal of Practical Surgery 2022;42:585-9.
28. Hartwig W, Hackert T, Hinz U, et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg 2011;254:311-9. [Crossref] [PubMed]
29. Kang HW, Seo SP, Kim WT, et al. Impact of the ASA Physical Status Score on Adjuvant Chemotherapy Eligibility and Survival of Upper Tract Urothelial Carcinoma Patients: a Multicenter Study. J Korean Med Sci 2017;32:335-42. [Crossref] [PubMed]
30. Nishibeppu K, Sakuramoto S, Matsui K, et al. Dismal prognosis of elderly gastric cancer patients who underwent gastrectomy with American Society of Anesthesiologists (ASA) 3. Langenbecks Arch Surg 2022;407:3413-21. [Crossref] [PubMed]
31. Xu HX, Liu L, Xiang JF, et al. Postoperative serum CEA and CA125 levels are supplementary to perioperative CA19-9 levels in predicting operative outcomes of pancreatic ductal adenocarcinoma. Surgery 2017;161:373-84. [Crossref] [PubMed]
32. van Manen L, Groen JV, Putter H, et al. Elevated CEA and CA19-9 serum levels independently predict advanced pancreatic cancer at diagnosis. Biomarkers 2020;25:186-93. [Crossref] [PubMed]
33. Haemmerle M, Stone RL, Menter DG, et al. The Platelet Lifeline to Cancer: Challenges and Opportunities. Cancer Cell 2018;33:965-83. [Crossref] [PubMed]
34. Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost 2011;9:237-49. [Crossref] [PubMed]
35. Xu SS, Li S, Xu HX, et al. Haemoglobin, albumin, lymphocyte and platelet predicts postoperative survival in pancreatic cancer. World J Gastroenterol 2020;26:828-38. [Crossref] [PubMed]
36. La Torre M, Ziparo V, Nigri G, et al. Malnutrition and pancreatic surgery: prevalence and outcomes. J Surg Oncol 2013;107:702-8. [Crossref] [PubMed]
37. Ruiz-Tovar J, Martín-Pérez E, Fernández-Contreras ME, et al. Impact of preoperative levels of hemoglobin and albumin on the survival of pancreatic carcinoma. Rev Esp Enferm Dig 2010;102:631-6. [Crossref] [PubMed]
38. Hayashi M, Kobayashi D, Takami H, et al. Albumin-Globulin Ratio Indicates the Survival Outcome of Pancreatic Cancer Cases Who Underwent Preoperative Treatment and Curative Surgical Resection. Nutr Cancer 2023;75:1330-9. [Crossref] [PubMed]
39. Mantovani A, Cassatella MA, Costantini C, et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011;11:519-31. [Crossref] [PubMed]
40. Carnevale S, Ghasemi S, Rigatelli A, et al. The complexity of neutrophils in health and disease: Focus on cancer. Semin Immunol 2020;48:101409. [Crossref] [PubMed]
41. Murthy P, Singhi AD, Ross MA, et al. Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine. Front Immunol 2019;10:28. [Crossref] [PubMed]
42. Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood 2019;133:2159-67. [Crossref] [PubMed]
43. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539-45. [Crossref] [PubMed]
44. Merza M, Hartman H, Rahman M, et al. Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice With Severe Acute Pancreatitis. Gastroenterology 2015;149:1920-1931.e8. [Crossref] [PubMed]
45. Di Mitri D, Toso A, Chen JJ, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 2014;515:134-7. [Crossref] [PubMed]
46. Xi Y, Jing Z, Haihong L, et al. Analysis of T lymphocyte-related biomarkers in pancreatic cancer. Pancreatology 2020;20:1502-10. [Crossref] [PubMed]
47. Wang SC, Chou JF, Strong VE, et al. Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease-specific Survival in Resectable Gastroesophageal Junction and Gastric Adenocarcinoma. Ann Surg 2016;263:292-7. [Crossref] [PubMed]
48. Xiao Y, Xie Z, Shao Z, et al. Neutrophil and lymphocyte counts at diagnosis are associated with overall survival of pancreatic cancer: A retrospective cohort study. Medicine (Baltimore) 2016;95:e5024. [Crossref] [PubMed]
49. Fogar P, Sperti C, Basso D, et al. Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas 2006;32:22-8. [Crossref] [PubMed]
50. Zhang Y, Xu Y, Wang D, et al. Prognostic value of preoperative glucose to lymphocyte ratio in patients with resected pancreatic cancer. Int J Clin Oncol 2021;26:135-44. [Crossref] [PubMed]
51. Yang J, Wezeman M, Zhang X, et al. Human C-reactive protein binds activating Fcgamma receptors and protects myeloma tumor cells from apoptosis. Cancer Cell 2007;12:252-65. [Crossref] [PubMed]
52. Haruki K, Shiba H, Shirai Y, et al. The C-reactive Protein to Albumin Ratio Predicts Long-Term Outcomes in Patients with Pancreatic Cancer After Pancreatic Resection. World J Surg 2016;40:2254-60. [Crossref] [PubMed]
53. Stevens L, Pathak S, Nunes QM, et al. Prognostic significance of pre-operative C-reactive protein and the neutrophil-lymphocyte ratio in resectable pancreatic cancer: a systematic review. HPB (Oxford) 2015;17:285-91. [Crossref] [PubMed]
54. Szkandera J, Stotz M, Absenger G, et al. Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients. Br J Cancer 2014;110:183-8. [Crossref] [PubMed]
55. Shrotriya S, Walsh D, Bennani-Baiti N, et al. C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review. PLoS One 2015;10:e0143080. [Crossref] [PubMed]
56. Forrest LM, McMillan DC, McArdle CS, et al. Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. Br J Cancer 2004;90:1704-6. [Crossref] [PubMed]
57. Crumley AB, McMillan DC, McKernan M, et al. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 2006;94:637-41. [Crossref] [PubMed]
58. Roxburgh CS, Platt JJ, Leitch EF, et al. Relationship between preoperative comorbidity, systemic inflammatory response, and survival in patients undergoing curative resection for colorectal cancer. Ann Surg Oncol 2011;18:997-1005. [Crossref] [PubMed]
59. Iwai N, Okuda T, Sakagami J, et al. Neutrophil to lymphocyte ratio predicts prognosis in unresectable pancreatic cancer. Sci Rep 2020;10:18758. [Crossref] [PubMed]

(English Language Editor: L. Huleatt)