Active surveillance in metastatic pancreatic neuroendocrine tumors: A 20-year single-institutional experience.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous and indolent; systemic therapy is not essential for every patient with metastatic PanNET. The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis, if the patient has stable disease. However, specific factors that influence surveillance were not mentioned. In addition, data regarding the period of active surveillance in patients with metastatic PanNET are lacking. AIM: To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs (NF-PanNETs). METHODS: Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled. Time to disease progression (TTP) and time to initiation of systemic therapy were determined. RESULTS: Thirty-one (40.8%) patients had recurrent liver disease after R0 resection; 45 (59.2%) were diagnosed with liver metastasis. The median follow-up period was 42 mo and 90.7% patients were observed to have disease progression. The median TTP (mTTP) was 10 mo. Multivariate analysis showed that the largest axis of the liver metastasis > 5 mm (P = 0.04), non-resection of the primary tumor (P = 0.024), and T3-4 stage (P = 0.028) were associated with a shorter TTP. The mTTP in patients with no risk factors was 24 mo, which was significantly longer than that in patients with one (10 mo) or more (6 mo) risk factors (P < 0.001). A nomogram with three risk factors showed reasonable calibration, with a C-index of 0.603 (95% confidence interval: 0.47-0.74). CONCLUSION: Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors, and other patients progressed rapidly without treatment. Further studies with a larger sample size and a control group are needed.

Haemoglobin, albumin, lymphocyte and platelet predicts postoperative survival in pancreatic cancer.

BACKGROUND: Systemic inflammation and nutrition status play an important role in cancer metastasis. The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP), consisting of haemoglobin, albumin, lymphocytes, and platelets, is considered as a novel marker to reflect both systemic inflammation and nutrition status. However, no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection. AIM: To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients. METHODS: The preoperative serum levels of hemoglobin, albumin, lymphocyte counts, and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection. The relationship between postoperative survival and the preoperative level of HALP was investigated. RESULTS: Low levels of HALP were significantly associated with lymph node metastasis (P = 0.002), poor tumor differentiation (P = 0.032), high TNM stage (P = 0.008), female patients (P = 0.005) and tumor location in the head of the pancreas (P < 0.001). Low levels of HALP were associated with early recurrence [7.3 mo vs 16.3 mo, P < 0.001 for recurrence-free survival (RFS)] and short survival [11.5 mo vs 23.6 mo, P < 0.001 for overall survival (OS)] in patients with resected pancreatic adenocarcinoma. A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location. CONCLUSION: Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.

SRPX2 and RAB31 are effective prognostic biomarkers in pancreatic cancer.

Introduction: SRPX2 and RAB31 play important roles in tumorigenesis and metastasis; however, their prognostic value in pancreatic cancer remains unclear. This study aimed to investigate the potential interactions and effects of SRPX2 and RAB31 on the diagnosis and prognosis of pancreatic cancer. Methods: The expression of SRPX2 and RAB31 in pancreatic tumor tissues and cells was evaluated through database mining of the Oncomine, Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and validated the results through immunohistochemistry (IHC) and Western blot in our clinical database. Protein-protein interactions were explored by immunofluorescence and Co-immunoprecipitation (Co-IP). Two hundred tissue microarray specimens from patients (79 training and 121 validation), who underwent curative pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) were used. Additionally, the association between the SRPX2 and RAB31 and prognosis of PDAC patients after surgery was analyzed. Results: The expression of SRPX2 and RAB31 was highly increased in pancreatic cancer, and there was a significant positive correlation between these two proteins. Co-IP showed the direct interaction between SRPX2 and RAB31. Kaplan-Meier analysis showed that positive expression of SRPX2 and RAB31 was associated with reduced disease-free survival (DFS) and overall survival (OS) of PDAC patients in the training set and the validation sets. Furthermore, multivariate analysis indicated that the 8th edition TNM stage and combination of SRPX2 and RAB31 were independent prognostic factors that associated with OS and DFS in the training, and the validation sets, respectively. Conclusions: The combination of SRPX2 and RAB31 can be important markers for the prognosis of pancreatic cancer.

Neoadjuvant Therapy is Essential for Resectable Pancreatic Cancer.

BACKGROUND: Awareness of the benefits of neoadjuvant therapy is increasing, but its use as an initial therapeutic option for patients with resectable pancreatic cancer remains controversial, especially for those patients without high-risk prognostic features. Even for patients with high-risk features who are candidates to receive neoadjuvant therapy, no standard regimen exists. METHODS: In this review, we examined available data on the neoadjuvant therapy in patients with resectable pancreatic cancer, including prospective studies, retrospective studies, and ongoing clinical trials, by searching PubMed/MEDLINE, ClinicalTrials.gov, Web of Science, and Cochrane Library. The characteristics and results of screened studies were described. RESULTS: Retrospective and prospective studies with reported results and ongoing randomized studies were included. For patients with resectable pancreatic cancer, neoadjuvant therapy provides benefits such as increased survival, decreased risk of comorbidities and mortality, and improved cost-effectiveness due to an increased completion rate of multimodal treatment. Highly active regimens such as FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel are considered acceptable therapeutic regimens. Additionally, platinum-containing regimens other than FOLFIRINOX are acceptable for selected patients. Other therapies, such as chemoradiation treatment, immuno-oncology agents, and targeted therapies are being explored and the results are highly anticipated. CONCLUSION: This review highlights the benefits of neoadjuvant therapy for resectable pancreatic cancer. Some regimens are currently acceptable, but need more evidence from well-designed clinical trials or should be used after being carefully examined by a multidisciplinary team.

Tumor-Infiltrating NETs Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Tumor-infiltrating neutrophils (TINs) indicate poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). Activated neutrophils can generate neutrophil extracellular traps (NETs). Little is known about the presence and prognostic significance of tumor-infiltrating NETs in PDAC. METHODS: This study enrolled 317 patients, in two independent sets (training and validation), who underwent curative pancreatectomy for PDAC in Shanghai Cancer Center. TINs and NETs were identified by immunohistochemical staining for CD15 and citrullinated histone H3, respectively. The relationship between clinicopathological features and outcomes was analyzed. Accuracy of prognostic prediction models was evaluated using concordance index (C-index) and Akaike information criterion (AIC). RESULTS: NETs were associated with OS (both, P < 0.001) and RFS (both, P < 0.001) in the training and validation sets. Tumor-infiltrating NETs predicted poor postsurgical survival of patients with PDAC. Moreover, multivariate analysis identified NETs and AJCC TNM stage as two independent prognostic factors for OS and RFS. Combination of NETs with the 8th edition TNM staging system (C-index, 0.6994 and 0.6669, respectively; AIC, 1067 and 1126, respectively) generated a novel model that improved the predictive accuracy for survival in both sets (C-index, 0.7254 and 0.7117, respectively; AIC, 1047 and 1102, respectively). The model combining presence of NETs with the 7th edition AJCC TNM staging system also had improved predictive accuracy. CONCLUSIONS: NETs were an independent prognostic factor in PDAC and incorporation of NETs along with the standard TNM stating system refined risk-stratification and predicted survival in PDAC with improved accuracy.

Angiogenesis in pancreatic cancer: current research status and clinical implications.

Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.

Arpin downregulation is associated with poor prognosis in pancreatic ductal adenocarcinoma.

INTRODUCTION: Arpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the prognostic value of Arpin in pancreatic ductal adenocarcinoma (PDAC) remains unknown. MATERIALS AND METHODS: We analyzed the gene expression of ARPIN using the GEO dataset (GSE71989) and validated the results by immunohistochemistry (IHC) and Western blot in our clinical database. Tissue microarray specimens from 214 patients who underwent curative pancreatectomy for PDAC were used. The tumors that expressed high and low levels of Arpin were compared with patient outcome using Kaplan-Meier curves and the multivariate Cox proportional hazard regression model. IHC was then used in 43 paired primary tumor tissues and metastasis tissues to detect the expression of Arpin. RESULTS: Arpin had low expression in the tumor tissue compared with the paracancerous tissue in PDAC. Patients with low intratumoral Arpin expression had worse overall survival (OS) and recurrence-free survival (RFS) than patients with high expression in the training set (p < 0.001, p < 0.001) and validation set (p < 0.001, p < 0.001). The multivariate analysis revealed that the 8th edition TNM stage and Arpin expression were independent prognostic factors associated with OS and RFS in the training and validation sets, respectively. Arpin had lower expression in the metastasis tissues than in the primary tumors of patients with PDAC (p = 0.048). CONCLUSION: The Arpin level is an independent prognostic factor that can be a potential predictor to aid in the management of PDAC.

Zinc finger E-box-binding homeobox 1 mediates aerobic glycolysis via suppression of sirtuin 3 in pancreatic cancer.

AIM: To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism. METHODS: Endogenous zinc finger E-box binding homeobox-1 (ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1 (MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3 (SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatin-immunoprecipitation assays. RESULTS: ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION: ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.

The Significance of Liquid Biopsy in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. The 5-year survival rate for PDAC remains low because it is always diagnosed at an advanced stage and it is resistant to therapy. A biomarker, which could detect asymptomatic premalignant or early malignant tumors and predict the response to treatment, will benefit patients with PDAC. However, traditional biopsy has its limitations. There is an urgent need for a tumor biomarker that could easily and repeatedly sample and monitor, in real time, the progress of tumor development. Liquid biopsy could be a tool to assess potential biomarkers. In this review, we focused on the latest discoveries and advancements of liquid biopsy technology in pancreatic cancer research and demonstrated how this technology is being used in clinical applications.

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

Postoperative serum CA19-9, CEA and CA125 predicts the response to adjuvant chemoradiotherapy following radical resection in pancreatic adenocarcinoma.

OBJECTIVE: To evaluate the prediction of benefits from adjuvant chemoradiotherapy by postoperative serum CA19-9, CA125 and CEA. METHODS: The relations between benefits from adjuvant chemoradiotherapy and levels of postoperative serum CA19-9, CA125 and CEA were investigated in 804 pancreatic adenocarcinoma patients who received radical resection. RESULTS: Adjuvant chemoradiotherapy was an independent factor for late recurrence [12.2 vs. 8.5 months, P = 0.001 for recurrence free survival (RFS)] and long survival [23.7 vs. 17.0 months, P < 0.001 for overall survival (OS)] in resected pancreatic adenocarcinoma. Postoperative serum CA19-9, CA125 and CEA were independent risk predictors for poor surgical outcome in pancreatic adenocarcinoma (P < 0.001 for all). Adjuvant chemradiotherapy (hazard ratio: 0.359, 95% confidence interval: 0.253-0.510, P < 0.001 for OS; hazard ratio: 0.522, 95% confidence interval: 0.387-0.705, P < 0.001 for RFS) were confirmed to improve the surgical outcome in patients with abnormal levels of any one of the three postoperative markers, but not in patients with normal levels of the three postoperative markers. In the subgroup of patients with negative lymph node, its improvement of surgical outcome was also significant in patients with abnormal levels of any one of postoperative serum CA19-9, CA125 and CEA (hazard ratio: 0.412, 95% confidence interval: 0.244-0.698, P = 0.001 for OS; hazard ratio: 0.546, 95% confidence interval: 0.352-0.847, P = 0.007 for RFS). CONCLUSION: Postoperative serum CA19-9, CA125 and CEA could serve as predictors of response for adjuvant chemoradiotherapy even if the status of lymph nodes is negative.

A novel scoring system predicts postsurgical survival and adjuvant chemotherapeutic benefits in patients with pancreatic adenocarcinoma: Implications for AJCC-TNM staging.

BACKGROUND: We evaluated the application of the latest 8th American Joint Committee on Cancer (AJCC) staging system in Chinese patients and determined whether the addition of biologic markers could improve the prediction of postsurgical survival in pancreatic adenocarcinoma (PC). METHODS: This multicenter study involved 1,223 consecutive patients who underwent margin-negative pancreatectomy for PC. A scoring system was devised based on AJCC pathologic parameters and biologic markers and defined using a Cox proportional hazards model. Prognostic accuracies were evaluated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: The 8th edition AJCC staging system had a better survival distribution of PC with different stages and a similar C-index (0.62 in the training cohort, 0.60 in the validation cohort) than the 7th edition (0.59 in the training cohort, 0.58 in the validation cohort). Nevertheless, survival of resected patients with stage IIA or IIB disease was indistinguishable. Incorporation of postoperative carbohydrate antigen 19-9 (CA19-9) levels and tumor grade into the 8th edition AJCC staging system generated a scoring system with better predictive accuracy for overall survival (OS) (C-index of 0.73 and AIC of 4301.05 in the training cohort, C-index of 0.71 and AIC of 3309.23 in the validation cohort). More importantly, patients with median or higher scores experienced OS benefits from adjuvant chemotherapy. CONCLUSION: Postoperative CA19-9 levels and tumor grade are two well-known PC biologic markers that could be incorporated into a standard AJCC staging system to refine risk stratification and predict OS benefit from adjuvant chemotherapy in resected PC.

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis.

BACKGROUND: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC. DATA SOURCES: Electronic search of the PubMed, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival (OS). RESULTS: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry (IHC) was higher than that measured by polymerase chain reaction (PCR) (P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS (HR = 2.34; 95% CI: 1.78-3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3-4 group was higher than that in the T1-2 group (OR = 0.37; P = 0.001). CONCLUSIONS: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.

Strategies for pancreatic anastomosis after pancreaticoduodenectomy: What really matters?

BACKGROUND: The postoperative pancreatic fistula rate remains approximately 10-20% even in institutions treating a high-volume of pancreatic cases. The best strategy to restore the continuity between the pancreatic remnant and the digestive tract is still in debate. DATA SOURCES: Studies were identified by searching PubMed for studies published between January 1934 (when pancreaticogastrostomy was technically feasible) and December 2016. The following search terms were used: "duct-to-mucosa", "invagination", "pancreaticojejunostomy", "pancreaticogastrostomy," and "pancreaticoduodenectomy". The search was limited to English publications. RESULTS: Many technical methods have been developed and optimized to restore pancreaticoenteric continuity, including pancreaticojejunostomy, pancreaticogastrostomy, and stented drainage of the pancreatic duct, among other modifications. Researchers have also attempted to decrease the postoperative pancreatic fistula after pancreaticoduodenectomy by using fibrin glue and somatostatin analogues. However, no significant decrease in postoperative pancreatic fistula has been observed in most of these studies, and only an external pancreatic duct stent has been found to decrease the leakage rate of pancreatic anastomosis after pancreaticojejunostomy. CONCLUSION: Pancreatic surgeons should choose a suitable technique according to the characteristics of individual cases.

RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling.

Pancreatic cancer is a lethal disease with a high metastatic potential. In our previous study, we identified a specific subgroup of patients with pancreatic cancer with a serum signature of carcinoembryonic antigen (CEA)+/cancer antigen (CA)125+/CA19-9 ≥1,000 U/ml. In this study, by using high-throughput screening analysis, we found that receptor-interacting protein kinases 4 (RIPK4) may be a key molecule involved in the high metastatic potential of this subgroup of patients with pancreatic cancer. A high RIPK4 expression predicted a poor prognosis and promoted pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway. Moreover, RIPK4 activated the RAF1/MEK/ERK pathway by regulating proteasome-mediated phosphatidylethanolamine binding protein 1 (PEBP1) degradation. The suppression of PEBP1 degradation eliminated the RIPK4-induced activation of RAF1/MEK/ERK signaling and pancreatic cancer cell migration or invasion. Thus, on the whole, the findings of this study indicated that RIPK4 was upregulated in the subgroup of pancreatic cancer with a high metastatic potential. RIPK4 overexpression promoted pancreatic cancer cell migration and invasion via the PEBP1 degradation-induced activation of the RAF1/MEK/ERK pathway.

Intrinsic Contact Between T and N Classifications in Resected Well-Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification. METHODS: Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006-2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed. RESULTS: In cohorts 1 and 2, tumor size (2-4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data. CONCLUSIONS: N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs.

Postoperative serum CEA and CA125 levels are supplementary to perioperative CA19-9 levels in predicting operative outcomes of pancreatic ductal adenocarcinoma.

BACKGROUND: Carbohydrate antigen (CA19-9) is a well-established marker to monitor disease status after resection of pancreatic cancer. However, few serum markers have been reported to improve the prognostic ability of postoperative CA19-9, especially in patients with normal postoperative CA19-9. METHODS: A total of 353 patients with pancreatic ductal adenocarcinoma treated by radical resection were reviewed retrospectively, and a prospective cohort including 142 patients with resectable pancreatic head carcinoma was analyzed as a validation cohort. Perioperative CA19-9 and postoperative serum markers (CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) were investigated. RESULTS: Patients with postoperative normalization of CA19-9 had improved survival times (recurrence-free survival: 11.9 months; overall survival: 22.5 months) compared with those with decreased but still elevated postoperative CA19-9 (recurrence-free survival: 6.8 months, P < .001; overall survival: 13.5 months, P < .001) or those with increased postoperative CA19-9 (recurrence-free survival: 3.5 months, P < .001; overall survival: 7.9 months, P < .001), which was similar to those with consistently normal CA19-9 during perioperative periods (recurrence-free survival: 10.6 months, P = .799; overall survival: 24.1 months, P = .756). Normal postoperative CA19-9 levels were an independent indicator for a positive outcome after operation, regardless of preoperative CA19-9 levels. Elevated postoperative CEA and CA125 were identified further as independent risk factors for patients with normal postoperative CA19-9, while elevated postoperative CA125 and nondecreased postoperative CA19-9 were independent prognostic markers for patients with elevated postoperative CA19-9. CONCLUSION: The postoperative monitoring of CEA and CA125 provided prognostic significance to the measurement of CA19-9 in pancreatic cancer after resection.

Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 ≥ 1,000 U/mL.

Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 ≥ 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver-genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin-1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53(R172H) upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy.