Effect of preoperative biliary drainage on peripheral circulating tumor cells after pancreaticoduodenectomy in patients with resectable periampullary carcinoma and obstructive jaundice

Introduction

Periampullary carcinoma is a group of malignancies with poor prognosis, typically classified by anatomical origin into pancreatic head cancer, distal cholangiocarcinoma, and duodenal papillary carcinoma (1,2). Some patients present with obstructive jaundice accompanied by impaired liver function and internal milieu disturbances (3). In such cases, preoperative biliary drainage (PBD) is often performed to alleviate biliary obstruction prior to curative pancreaticoduodenectomy (PD) (4,5). However, the utility of PBD remains contentious, as some scholars argue that its detrimental effects may outweigh the benefits under certain conditions—such as inducing cholangitis or pancreatitis, causing tissue edema and adhesions that complicate surgery, or even facilitating tumor dissemination via stent migration (6-8). Consequently, several critical issues regarding PBD remain unresolved.

With the advancement of precision medicine, the detection and analysis of circulating tumor cells (CTCs) in peripheral blood have gained increasing attention in periampullary carcinoma. Perioperative CTC levels play a crucial role in assessing resectability, predicting postoperative recurrence, and evaluating patient survival (9). Nevertheless, high-quality clinical evidence regarding the impact of PBD on postoperative CTC dynamics is still lacking. This knowledge gap represents a key issue in evaluating the true value of PBD.

Therefore, leveraging clinical data from patients with periampullary malignancies who underwent PD at our institution, we conducted a retrospective cohort study to explore the effect of PBD on postoperative CTC levels in patients with obstructive jaundice. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-170/rc).

Methods

Participants

Retrospective analysis was conducted on the clinical data of 125 patients with ampullary malignancies who underwent PD at Beijing Friendship Hospital of Capital Medical University from June 2017 to October 2024. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (No. 2022-P2-104-01). Individual consent for this retrospective analysis was waived.

We included the following patients: (I) adults aged ≥18 years; (II) patients with preoperative imaging assessment indicating resectable periampullary malignancy, defined with reference to the National Comprehensive Cancer Network guidelines: tumors that had not invaded the superior mesenteric artery, celiac trunk, or proper hepatic artery; had not invaded the superior mesenteric vein and portal vein; or had invaded the above but to an extent of <180° and with a clear portal vein contour without deformation; (III) patients with jaundice-related symptoms such as visible jaundice or pruritus; (IV) patients with postoperative pathology showing the pathological types of pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, or duodenal papillary carcinoma, with the pathological types divided into biliopancreatic carcinoma or intestinal adenocarcinoma.

Exclusion criteria were as follows: (I) presence of cholangitis or pancreatitis at the time of admission; (II) patients who had undergone biliary drainage prior to hospital admission; (III) postoperative pathology showing invasive intraductal papillary mucinous neoplasms, primitive neuro-ectodermal tumors, and other non-biliopancreatic or intestinal types; (IV) preoperative evaluation showing the presence of distant metastases or borderline resectable tumors requiring neoadjuvant therapy (NAT); (V) presence of other concomitant primary malignant diseases; (VI) vital organ insufficiency or other concomitant serious diseases (e.g., severe cardiopulmonary insufficiency, liver insufficiency, etc.), making patients unsuitable for surgery; (VII) pregnancy; (VIII) refusal to participate in the study

Eventually, the study included 72 males and 53 females (median age: 61.75 years). These patients were divided according to the presence or absence of PBD into a PBD (n=70) and control (n=55) group.

Data collection and CTC detection methods

Clinical data, including patient demographics (sex, age), surgical procedure, postoperative pathological type, perioperative CTC levels, bilirubin-related biochemistry, and PBD approach, were collected. This study employed the Cytoplorare circulating tumor cell detection kit provided by GenoSaber Biotech Co., Ltd. (Nantong, China). The assay is based on a targeted probe labeling system: specific small-molecule probes bind to folate receptor-positive cells. After sufficient incubation, polymerase chain reaction (PCR) is used to amplify and quantify the oligonucleotide sequences contained within the small-molecule probes bound to the folate receptors. The results are reported in folate units (FU) per 3 mL, representing the relative content of folate receptor-positive CTCs in 3 mL of peripheral blood (10,11). The CTC sampling time points in this study were standardized as follows: preoperative CTCs were collected on the day after admission, and postoperative CTCs were collected one week after surgery. Perioperative CTC profiles comprised preoperative CTC count, post-PD CTC count, and the CTC difference (defined as postoperative CTC minus preoperative CTC). The qualitative stratification criteria were defined as follows: positive (>10.08 FU/mL), gray zone (suspected positive; 8.70–10.08 FU/mL), and negative (<8.70 FU/mL). All patients were followed up via outpatient visits or telephone interviews to monitor long-term survival and disease progression.

PBD and PD methods

Preoperative jaundice-reducing methods included endoscopic nasobiliary drainage (ENBD), percutaneous transhepatic cholangial drainage, or biliary stenting, all of which were performed by experienced endoscopists from the Department of Gastroenterology at our center.

All patients underwent open or laparoscopic PD conducted by an experienced chief surgeon at our center. Routine regional lymph node dissection was performed during the procedure. Digestive tract reconstruction was carried out using Child’s method.

Statistical analysis

SPSS v26.0 statistical software (IBM SPSS Inc., Armonk, NY, USA) and R programming language (version 3.6.3; https://www.r-project.org/) were used for data analysis. Baseline data of categorical or continuous variables were expressed as statistical description. Univariate between-group comparisons were performed using grouped Chi-squared tests or independent-samples t-tests. Donut charts showing the distribution of the patients’ chief complaints and overlay histograms showing the postoperative pathological characteristics of the PBD and control groups were computed and visualized using the R packages ggplot2 (3.3.6) and ggalluvial (0.12.3). Bean plots comparing the perioperative CTC values and preoperative bilirubin-related indicators between the PBD group and control group, as well as the bilirubin-related indicators between different PBD methods were computed using the R packages stats (4.2.1) and car (3.1-0), subjected to the Wilcoxon signed rank test, and visualized with the R package ggplot2 (version 3.3.3). Propensity score matching (PSM) and multiple linear regression were calculated using SPSS26.0. Binary univariate and multivariate logistic regression analyses of increased CTC difference were computed using the R packages rms (6.4.0) and ResourceSelection (0.3-5). All test statistics were described, and P<0.05 was considered statistically significant.

Results

Study population and patient characteristics

A total of 125 patients were enrolled, including 72 males and 53 females, with a median age of 61.75 years [interquartile range (IQR), 57–68 years]. Among them, 55 patients did not undergo PBD and were designated as the control group, while 70 patients received PBD. Of these, 29 underwent retrograde drainage via ERCP with stent placement, and 41 underwent antegrade drainage via percutaneous transhepatic cholangiographic drainage. Based on tumor location, there were 33 cases of pancreatic head cancer, 48 cases of duodenal papillary carcinoma, and 44 cases of distal cholangiocarcinoma.

The median total bilirubin (TB) level was 84.7 µmol/L (IQR, 18.66–229.49 µmol/L) at admission and 45.17 µmol/L (IQR, 17.99–133.0 µmol/L) preoperatively. The median direct bilirubin (DB) level was 50.33 µmol/L (IQR, 7.68–127.82 µmol/L) at admission and 23.75 µmol/L (IQR, 7.45–80.02 µmol/L) preoperatively. The median preoperative CTC count was 10.8 FU/mL (IQR, 6.55–16.55 FU/mL), decreasing to a median of 10.0 FU/mL (IQR, 7.4–14.4 FU/mL) postoperatively. The median change in CTC (ΔCTC, defined as postoperative minus preoperative) was 0.3 FU/mL (IQR, –4.1 to 3.7 FU/mL). Postoperative CTC levels decreased in 60 patients and increased in 65.

Preoperatively, 63 patients tested positive for CTCs, while 62 were negative or in the gray zone. Postoperatively, 51 patients were positive and 74 were negative or gray-zone. Dynamic qualitative analysis revealed that 85 patients had stable CTC status, 26 converted from positive to negative, and 14 converted from negative to positive (Table 1).

Chief complaints at presentation included abdominal or back pain (n=36), jaundice-related symptoms such as icteric sclera and changes in urine/stool color (n=57), incidentally detected periampullary masses on physical examination (n=26), and multiple nonspecific symptoms (n=6). All patients underwent laparoscopic or open PD. Postoperative pathology identified 79 cases as biliary-pancreatic-type carcinoma and 46 as intestinal-type adenocarcinoma. Perineural invasion was present in 37 controls and 38 PBD patients. Lymphovascular invasion was observed in 28 controls and 28 PBD patients. Vascular tumor thrombi were identified in 6 controls and 12 PBD patients (Figure 1).

Figure 1 Distribution of presenting symptoms and pathological characteristics in enrolled patients. (A) Donut chart of patient chief complaints and symptoms distribution; (B) stacked bar chart of postoperative pathological nerve invasion in the biliary drainage group and control group; (C) stacked bar chart of postoperative pathological vascular invasion in the biliary drainage group and control group; (D) stacked bar chart of postoperative vascular cancer thrombus in the biliary drainage group and control group. PBD, preoperative biliary drainage.

Univariate analysis of baseline characteristics and perioperative CTC indicators

No significant differences in gender, age, or pathological type were observed between the PBD and control groups (all P>0.05; Table 2). Similarly, bilirubin-related indicators—including admission and preoperative levels of TB and DB—showed no significant intergroup differences (Figure 2A).

Figure 2 Changes in bilirubin and circulating tumor cell levels before and after preoperative biliary drainage. (A) Comparison of mean values of basic bilirubin-related indexes between biliary drainage group and control group; (B) comparison of bilirubin before and after drainage by different biliary drainage method; (C) paired comparison of the results of bilirubin pre and post biliary drainage; (D) bean plot of comparison of preoperative CTC values and CTC differences. CTC, circulating tumor cell; DB, direct bilirubin; PBD, preoperative biliary drainage; TB, total bilirubin.

Within the PBD group, admission TB and DB levels did not differ between the antegrade and retrograde drainage subgroups. However, the antegrade subgroup demonstrated significantly lower postoperative TB and DB levels compared to the retrograde subgroup (all P<0.05; Figure 2B). Furthermore, both TB and DB decreased significantly following drainage intervention (P<0.05; Figure 2C), confirming effective jaundice relief.

Preoperative CTC levels did not differ significantly between the PBD and control groups [10.6 (IQR, 6.25–15.78) vs. 11.9 (IQR, 7.05–19.1) FU/mL; P=0.26]. However, postoperative CTC levels were significantly lower in the PBD group [8.4 (IQR, 6.23–10.0) vs. 13.7 (IQR, 11.05–19.65) FU/mL; P<0.001; Table 2, Figure 2A]. The ΔCTC was also significantly lower in the PBD group [–2.5 (IQR, –6.58 to 2.15) vs. 3.5 (IQR, –0.35 to 6.95) FU/mL; P<0.001; Table 2, Figure 2D]. Trend analysis showed CTC reduction in 45 PBD patients vs. 15 controls, and increase in 25 PBD vs. 40 controls (χ²=16.90, P<0.001). Postoperatively, 10 PBD patients were CTC-positive vs. 60 negative/gray-zone, while 41 controls were positive vs. 14 negative/gray-zone. Dynamic changes in CTC status differed significantly between groups (χ²=31.195, P<0.001; Table 2).

Multivariate analysis identifies PBD as an independent protective factor against postoperative CTC increase

To minimize the potential influence of confounding factors on the observed outcomes, this study employed PSM to control for baseline differences. Based on clinical expertise and existing literature, the following covariates were included for matching: gender, age, admission alanine aminotransferase (ALT), and admission white blood cell (WBC). A 1:1 matching protocol was performed between the experimental and control groups using a caliper width of 0.02. This process yielded a well-matched cohort of 110 cases. Post-matching assessment confirmed that all covariates achieved a standardized mean difference (SMD) of less than 0.1, indicating successful balancing of baseline characteristics. Univariate and multivariate binary logistic regression analyses incorporating tumor marker, bilirubin, pathology, PBD status, and laboratory examination values identified PBD and preoperative albumin as protective factors for decreased ΔCTC in univariate analysis [odds ratio (OR) =0.250, 95% confidence interval (CI): 0.112–0.557, P<0.001]. The results of multi-factor binary logistic regression analysis suggested that PBD was an independent protective factor against postoperative CTC increase (OR =0.211, 95% CI: 0.082–0.547, P=0.001; Table 3). Furthermore, we analyzed the differences in CTC changes among patients who underwent different biliary drainage procedures. The results indicated that CTC reduction was more pronounced in patients receiving PTCD compared to those undergoing ERCP (P=0.01; Table S1).

PBD is one of the factors influencing postoperative CTC levels

Multiple linear regression analysis, with postoperative CTC level as the dependent variable, identified PBD and preoperative CTC level as the primary determinants of postoperative CTC variation (model F=6.82, P<0.001, adjusted R²=0.494). PBD was independently associated with a significant reduction in postoperative CTC level (β=–0.374; mean reduction: –8.25 units; 95% CI: –11.42 to –5.08; P<0.001). Preoperative CTC level was a positive predictor of postoperative CTC (β=0.478; 95% CI: 0.34–0.67; P<0.001; Table 4). Initial TB also showed a significant association (B=0.039, P=0.03). Other variables, including age, tumor diameter, tumor markers, and operation time, were not significantly associated with postoperative CTC levels (all P>0.05).

Discussion

CTCs are tumor cells present in the human circulatory system, originating from primary tumors or metastatic lesions. They participate in blood circulation and possess capabilities such as chemoresistance and evasion of anti-tumor immune responses (12,13). Studies have confirmed that most CTCs are rapidly destroyed in the circulation, with approximately 2.5% capable of forming micro-metastases, and only 0.01% of these cells able to induce macro-metastases (14). The detection and enumeration of CTCs have clinical utility in PDAC and serve as a prognostic marker. A review and meta-analysis of 19 studies involving over 1,300 PDAC patients indicated that CTC positivity is associated with poorer progression-free survival (PFS) and overall survival (OS) (15-17). Meanwhile, numerous studies have established CTCs as a prognostic marker in patients eligible for surgical resection (12,18,19). CTCs also play a critical and clinically significant role in predicting early disease recurrence and selecting effective treatments (20-22). A 2022 study further demonstrated that the absolute CTC count after chemotherapy is negatively correlated with OS, and a reduction in CTC levels post-chemotherapy is significantly associated with prolonged OS in PDAC patients (23). Studies have shown that CTC-positive patients have significantly shorter OS and PFS compared to CTC-negative patients (17). Research by Kurihara et al. indicated a negative correlation between CTCs and survival time, with longer survival observed when chemotherapy reduced or eliminated CTC levels (23). These findings suggest that changes in CTC levels can reflect treatment efficacy and patient prognosis.

The dynamics of CTCs are influenced by a multifaceted array of factors. Clinically, the degree of differentiation and tumor-node-metastasis (TNM) stage of the primary tumor, alongside interventions like chemotherapy, targeted therapy, or surgery, can alter CTC counts by reducing the primary tumor burden. More significantly, the status of various immune cells plays a crucial role. Pro-tumorigenic N2 neutrophils markedly increase CTC counts (24). In conditions like obstructive jaundice, elevated systemic bile acids significantly modulate the immune landscape in ways that may favor CTC persistence. Bile acids can polarize neutrophils toward a pro-tumorigenic N2 phenotype and promote M2 macrophage polarization via the farnesoid X receptor (FXR) receptor, enhancing their immunosuppressive function (25,26). They also inhibit M1 macrophage antigen presentation and pro-inflammatory secretion (25). Furthermore, bile acids promote the accumulation and suppressive activity of myeloid derived suppressor cells (MDSCs) and can inhibit CD8⁺ T cell activity, thereby fostering an overall immunosuppressive network conducive to CTC survival and spread (26). Clinical observations of reduced CTC levels post-biliary drainage suggest the potential existence of specific pathways such as a “bile acid-N2-CTC” axis or a “bile acid-MDSC-CTC” pathway. Current indications for PBD include cholangitis, delayed surgery, and jaundice relief in patients scheduled for NAT (27). However, the use of PBD in periampullary cancer patients remains controversial in clinical practice (28). With advancements in ERCP and PTC techniques, PBD once became a routine international practice (29-31), with the currently accepted duration for biliary drainage being 4–6 weeks (32,33). Nevertheless, some scholars argue that PBD may cause more harm than benefit under certain conditions, such as inducing cholangitis or pancreatitis, causing local tissue edema and adhesions that complicate surgery, or even facilitating tumor dissemination via stent migration (6-8). Clinicians holding this view may adopt a more conservative approach toward PBD.

At our center, patients with obstructive jaundice due to periampullary malignancies routinely receive hepatoprotective and choleretic medications. Those with poor preoperative general condition or severe obstructive jaundice undergo PBD in addition to pharmacological therapy. Our previous single-center retrospective study on the value of jaundice relief yielded non-inferior outcomes. The impact of jaundice relief on tumor recurrence and patient survival will be a focus of our future research. Existing clinical studies across multiple tumor types have shown that elevated postoperative CTC levels are significantly correlated with adverse prognosis events such as tumor recurrence and metastasis. Therefore, we consider that postoperative CTC levels may, to some extent, reflect prognostic trends in patients. Therefore, we conducted this exploratory single-center retrospective study. The results demonstrated a clear trend: in patients with well-balanced baseline characteristics, those who underwent PBD had significantly lower postoperative CTC levels and a more marked reduction in CTCs compared to the control group. These findings suggest that PBD does not increase such risks. Hence, a more proactive attitude toward PBD should be adopted for these patients. Furthermore, for patients presenting with obstructive jaundice and high CTC levels, biliary drainage may not only relieve obstruction and improve general condition but also reduce postoperative CTCs. For such patients, PBD should be more actively considered. It should be emphasized that this study only examined the relationship between PBD and CTC levels, and does not conclude that patients receiving PBD have a better prognosis. This is primarily due to the single-center retrospective design of our study and the currently limited prognostic follow-up data available. More reliable conclusions to guide clinical practice will require future prospective, large-scale studies providing higher levels of evidence.

As an exploratory single-center retrospective study, this research has several limitations. For instance, the sample size is small, and although baseline characteristics were well-balanced between groups, biases due to insufficient sample size may exist. Additionally, due to technical constraints, the included cases lacked further CTC omics-related results, preventing correlation with basic medical research from transcriptomic and epigenomic perspectives. Nevertheless, we are already conducting further studies with expanded sample sizes and omics analyses. We will continue to explore the relationship between obstructive jaundice and CTCs, striving to provide more valuable clinical evidence for informing treatment strategies in relevant patients.

Conclusions

In summary, this study demonstrates that PBD is associated with a significantly greater reduction in postoperative CTC levels compared to no drainage. Consequently, concerns regarding potential postoperative CTC elevation should not preclude the use of PBD in the preoperative management of patients with obstructive jaundice and periampullary carcinoma.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-170/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-170/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-170/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-170/coif). The authors have 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (No. 2022-P2-104-01). 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, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin 2021;71:7-33. [Crossref] [PubMed]
2. Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018;391:1023-75. [Crossref] [PubMed]
3. Cui L, Yu H, Sun Q, et al. Effects of body mass index and serum albumin on overall survival in patients with cancer undergoing pancreaticoduodenectomy: a single-center retrospective cohort study. World J Surg Oncol 2022;20:221. [Crossref] [PubMed]
4. Clements WD, Parks R, Erwin P, et al. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 1996;39:587-93. [Crossref] [PubMed]
5. Gao Z, Wang J, Shen S, et al. The impact of preoperative biliary drainage on postoperative outcomes in patients with malignant obstructive jaundice: a retrospective analysis of 290 consecutive cases at a single medical center. World J Surg Oncol 2022;20:7. [Crossref] [PubMed]
6. Ozgun YM, Colakoglu MK, Oter V, et al. Biliary Stenting Prior to Pancreaticoduodenectomy and its Effects on Postoperative Outcome. Twenty Years of Experience with 805 Patients. Arch Iran Med 2021;24:771-8. [Crossref] [PubMed]
7. Park BK, Jeon TJ, Jayaraman V, et al. Endoscopic Retrograde Cholangiopancreatography in Patients with Previous Pancreaticoduodenectomy: A Single-Center Experience. Dig Dis Sci 2016;61:293-302. [Crossref] [PubMed]
8. Tsuchikawa T, Hirano S, Tanaka E, et al. Operative and perioperative management experience for hepatobiliary malignancies following ERCP-related pancreatitis. Hepatogastroenterology 2013;60:1360-4.
9. Martini V, Timme-Bronsert S, Fichtner-Feigl S, et al. Circulating Tumor Cells in Pancreatic Cancer: Current Perspectives. Cancers (Basel) 2019;11:1659. [Crossref] [PubMed]
10. Ma M, Xu S, Han B, et al. A retrospective diagnostic test study on circulating tumor cells and artificial intelligence imaging in patients with lung adenocarcinoma. Ann Transl Med 2022;10:1339. [Crossref] [PubMed]
11. He YG, Zheng L, Gao MF, et al. A preliminary study of the clinical significance of folate receptor-positive circulating tumor cell in the management of hepatobiliary-pancreatic cancers. Transl Cancer Res 2020;9:6700-9. [Crossref] [PubMed]
12. Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell 2006;127:679-95. [Crossref] [PubMed]
13. Kim YN, Koo KH, Sung JY, et al. Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol 2012;2012:306879. [Crossref] [PubMed]
14. Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998;153:865-73. [Crossref] [PubMed]
15. Han L, Chen W, Zhao Q. Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis. Tumour Biol 2014;35:2473-80. [Crossref] [PubMed]
16. Pang TCY, Po JW, Becker TM, et al. Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications. Pancreatology 2021;21:103-14. [Crossref] [PubMed]
17. Wang Y, Yu X, Hartmann D, et al. Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis. HPB (Oxford) 2020;22:660-9. [Crossref] [PubMed]
18. Park Y, Jun HR, Choi HW, et al. Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma. Sci Rep 2021;11:1644. [Crossref] [PubMed]
19. Zhu P, Liu HY, Liu FC, et al. Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients. Cancer Control 2021;28:10732748211027163. [Crossref] [PubMed]
20. Court CM, Ankeny JS, Sho S, et al. Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer. Ann Surg Oncol 2018;25:1000-8. [Crossref] [PubMed]
21. Effenberger KE, Schroeder C, Hanssen A, et al. Improved Risk Stratification by Circulating Tumor Cell Counts in Pancreatic Cancer. Clin Cancer Res 2018;24:2844-50. [Crossref] [PubMed]
22. Poruk KE, Blackford AL, Weiss MJ, et al. Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2017;23:2681-90. [Crossref] [PubMed]
23. Kurihara T, Itoi T, Sofuni A, et al. Detection of circulating tumor cells in patients with pancreatic cancer: a preliminary result. J Hepatobiliary Pancreat Surg 2008;15:189-95. [Crossref] [PubMed]
24. Szczerba BM, Castro-Giner F, Vetter M, et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 2019;566:553-7. [Crossref] [PubMed]
25. Varanasi SK, Chen D, Liu Y, et al. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer. Science 2025;387:192-201. [Crossref] [PubMed]
26. Sun R, Zhang Z, Bao R, et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J Hepatol 2022;77:453-66. [Crossref] [PubMed]
27. Nehme F, Lee JH. Preoperative biliary drainage for pancreatic cancer. Dig Endosc 2022;34:428-38. [Crossref] [PubMed]
28. El-Haddad HM, Sabry AA, Shehata GM. Endoscopic versus percutaneous biliary drainage for resectable pancreatic head cancer with hyperbilirubinemia and impact on pancreaticoduodenectomy: A randomized controlled study. Int J Surg 2021;93:106043. [Crossref] [PubMed]
29. Lyu Y, Li T, Cheng Y, et al. Endoscopic ultrasound-guided vs ERCP-guided biliary drainage for malignant biliary obstruction: A up-to-date meta-analysis and systematic review. Dig Liver Dis 2021;53:1247-53. [Crossref] [PubMed]
30. Lai EC, Lau SH, Lau WY. The current status of preoperative biliary drainage for patients who receive pancreaticoduodenectomy for periampullary carcinoma: a comprehensive review. Surgeon 2014;12:290-6. [Crossref] [PubMed]
31. van der Gaag NA, Rauws EA, van Eijck CH, et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010;362:129-37. [Crossref] [PubMed]
32. Costa Santos M, Cunha C, Velho S, et al. Preoperative biliary drainage in patients performing pancreaticoduodenectomy : guidelines and real-life practice. Acta Gastroenterol Belg 2019;82:389-95.
33. Shin SH, Han IW, Ryu Y, et al. Optimal timing of pancreaticoduodenectomy following preoperative biliary drainage considering major morbidity and postoperative survival. J Hepatobiliary Pancreat Sci 2019;26:449-58. [Crossref] [PubMed]