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Background: Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC., Methods: Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression., Results: SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival., Conclusions: Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory human malignancies. F-box only proteins (FBXO) are the core components of SKP1-cullin 1-F-box E3 ubiquitin ligase, which have been reported to play crucial roles in tumor initiation and progression via ubiquitination-mediated proteasomal degradation. However, the clinical implications and biological functions of FBXOs in PDAC have not been fully clarified. Herein we perform a comprehensive analysis for the clinical values and functional roles of FBXOs in PDAC using different public databases. We found that FBXO1 (CCNF), FBXO20 (LMO7), FBXO22, FBXO28, FBXO32, and FBXO45 (designated six-FBXOs) were robustly upregulated in PDAC tissues, which predicted an adverse prognosis of PDAC patients. There was a significant correlation between the expression levels of six-FBXOs and the clinicopathological features in PDAC. The transcriptional levels of six-FBXOs were subjected to the influence of promoter methylation levels. There were more than 40% genetic alterations and mutations of six-FBXOs, which affected the clinical outcome of PDAC patients. Furthermore, the expression of six-FBXOs was associated with immune infiltrations and activated status, including B cells, CD8 + T cells, CD4 + T cells, NK cells, macrophages, and dendritic cells. The functional prediction revealed that the six-FBXOs were involved in ubiquitination-related pathways and other vital signaling pathways, such as p53, PI3K/Akt, and Hippo pathway. Therefore, six-FBXOs are the promising prognostic biomarkers or potential targets for PDAC diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Liu, Cui, Wang, Hua, Gao and Liao.)

Purpose: The insufficient clearance of regional lymph nodes and unsatisfactory R0 resection rate may result in the metastasis of left-sided pancreatic ductal adenocarcinoma (PDAC) after conventional distal pancreatosplenectomy (CDPS). Radical antegrade modular pancreatosplenectomy (RAMPS) was designed to achieve R0 resection more successfully with better lymph-node clearance; however, there is still insufficient evidence of its short- and long-term results to confirm its superiority. We conducted this study to compare the efficiency of these two procedures., Methods: The subjects of this retrospective analysis were 103 patients with left-sided PDAC who underwent either RAMPS (n = 46) or CDPS (n = 57). We assessed perioperative data and surgical information and used univariate and multivariate analyses to identify prognostic factors for survival., Results: There were no significant differences in baseline data between the groups. RAMPS was associated with a significantly shorter hospital stay (12.11 days vs. 22.98 days; P < 0.001), and significantly less blood loss (451.09 ml vs. 764.04 ml, P = 0.002), as well as a significantly lower rate of blood transfusion (15.22% vs. 33.33%, P = 0.035). RAMPS and CDPS had comparable perioperative complication rates. Moreover, RAMPS achieved more effective lymph-node retrieval (17.87 vs. 10.23; P < 0.001). The RAMPS group had a higher overall survival (OS) rate (28.73 months vs. 18.30 months; P = 0.003) and a higher disease-free survival (DFS) rate (21.97 months vs. 9.40 months; P < 0.001)., Conclusion: RAMPS achieved better survival and surgical outcomes than CDPS for patients with left-sided PDAC.

Objective To investigate the expression of Cripto-1 in pancreatic cancer and to analyze its clinical significance. Methods Cripto-1 expression in normal pancreas,pancreatic cancer and adjacent non-tumor tissues,chronic pancreatitis tissues and other related tissues was evaluated using immunohistochemistry.The association of Cripto-1 expression with the clinicopathological characteristics and the prognostic value of Cripto-1 in patients with pancreatic cancer were analyzed. Results The expression of Cripto-1 was higher in chronic pancreatitis tissues,pancreatic cancer and its metastases than in normal pancreas(P=0.019,P=0.025,and P=0.018,respectively).Cripto-1 overexpression was correlated with poorly differentiated pancreatic cancer.The patients with Cripto-1 upregulation had shorter median survival time(8 months vs.16 months,χ 2 =4.787,P=0.029).However,multivariate analysis failed to demonstrate overexpression of Cripto-1 an independent prognostic indicator in patients with pancreatic cancer(HR=1.341,95% CI=0.800-2.248,P=0.266).Conclusions Cripto-1 may play an important role in the development and progression of pancreatic cancer.It can be a potential prognostic biomarker for patients with pancreatic cancer.

Pancreatic cancer is one of the most lethal tumors across the world with an overall 5-year survival rate of 9%, and great efforts have been devoted in early diagnosis and treatment in the past decades. Competing endogenous RNAs are novel and specific regulatory mechanisms of gene expression, and researches have indicated its important roles in tumor regulation. In this study, we explored the circ-0050102 expression in pancreatic cancer and its impacts on tumor malignant phenotypes and further investigated the correlations among circ-0050102, miR-1182 and NPSR1. Results of real-time quantitative PCR showed that circ-0050102 expressed higher in pancreatic cancers compared with that in adjacent normal tissues. In cell functional experiment, downregulation of circ-0050102 could suppress cell proliferation, migration and invasion ability, boost cell apoptosis and arrest cell cycle in both PANC-1 and CFPAC-1 cells. Furthermore, allogeneic transplantation in nude mice was performed and results showed that the inhibition of circ-0050102 could slow down tumor formation in vivo. Mechanism research suggested that circ-0050102 could downregulate miR-1182, while miR-1182 could not influence the expression of circ-0050102, and miR-1182 could directly target at NPSR1 and suppress it. Moreover, circ-0050102 could reverse the effects of si-NPSR1 on pancreatic cancer cells. In conclusion, we identified that circ-0050102 played an important role in promoting pancreatic cancer by regulating the miR-1182/NPSR1 pathway., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

CDHR5 has been reported to play key roles in carcinogenesis of various cancers, but its roles in pancreatic cancer have not been reported. The present study was designed to investigate its clinical value in pancreatic ductal adenocarcinoma (PDAC). Tissue microarray-based immunohistochemistry was performed to analyse the correlation between CDHR5 expression and clinical and pathological features of PDAC, as well as the CDHR5 expression during tumour progression. Cell function assays were performed to investigate CDHR5's effects on PDAC cells. Moreover, qRT-PCR was applied to investigate the expression of CDHR5 isoforms in PDAC cells. Expression of CDHR5 was higher on the membrane of PDAC cells. This high expression level was associated with shorter overall survival of PDAC patients and was identified as an independent prognostic factor for overall survival by multivariate Cox regression analysis. In addition, expression level of CDHR5 presented an increased trend in the occurrence and progression of PDAC. Cell experiment suggested that CDHR5 could notably promote invasion and migration of PDAC cells. Moreover, analysis of CDHR5 isoforms indicated CDHR5-L was the major isoform expressed in PDAC cell lines. CDHR5 appears to be a promising and novel prognostic factor for PDAC, and its promotion in PDAC metastasis might be ascribed to the isoform CDHR5-L., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-β1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-β1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-β1 and GM-CSF had the highest increase. Based on the above results, TGF-β1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-β1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a devastating prognosis. The performance of clinicopathologic parameters and molecules as prognostic factors remains limited and inconsistent. The present study aimed to construct a multi-molecule biomarker panel to more accurately predict post-resectional prognosis of PDAC patients., Methods: Firstly, a novel computational strategy integrating prognostic evidence from omics and literature on the basis of bioinformatics prediction (CIPHER) to generate the network, was designed to systematically identify potential high-confidence PDAC-related prognostic candidates. After specimens from 605 resected PDAC patients were retrospectively collected, 23 candidates were detected immunohistochemically in tissue-microarrays for the development cohort to construct a multi-molecule panel. Lastly, the panel was validated in two independent cohorts., Findings: According to the constructed five-molecule panel, disease-specific survival (DSS) was significantly poorer in high-risk patients than in low-risk ones in development cohort (HR 2.15, 95%CI 1.51-3.05, P<0.0001; AUC 0.67). In two validation cohorts, similar significant differences between the two groups were also observed (HR 3.18 and 3.31, 95%CI 1.89-5.37 and 1.78-6.16, All P<0.0001; AUC 0.72 and 0.73). In multivariate analyses, this panel was the sole prognosticator that was significant in each cohort. Furthermore, its predictive power for long-term survival, higher than its individual constituents, could be largely enhanced by combination with traditional clinicopathological variables. Finally, adjuvant chemotherapy (ACT) correlated with better DSS only in high-risk patients, uni- and multi-variately, in all the cohorts., Interpretation: The novel prognostic panel developed by a systematically network-based strategy presents strong ability in prediction of post-resectional survival of PDAC patients. Furthermore, panel-defined high-risk patients might benefit more from ACT., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.

A 57-year-old man underwent FDG PET/CT to evaluate a mass in the head of the pancreas. The imaged revealed mildly, nonuniformly increased activity in the mass, but the exact location of the activity could not be determined on the low-dose noncontrast CT portion of the study. On subsequent PET/MRI images acquired 60 minutes after the FDG PET/CT study, the increased activity was clearly localized on the cystic wall. The pathological examination showed that the lesion was intraductal papillary mucinous neoplasm of the pancreas with high degree of dysplasia.

Objective To examine the expression of cell division cycle associated 2 (CDCA 2) in pancreatic ductal adenocarcinoma (PDAC) and investigate its role in prognosis of PDAC patients. Methods This retrospective study included 155 PDAC patients who underwent surgical treatment and complete post-operative follow-up. Clinicopathologic data were collected through clinical database. Tissue microarray was constructed and immunohistochemistry was performed to detect CDCA2 expression in the PDAC tumor tissues and adjacent non-tumor tissues. Clinicopathological characteristics between high and low CDCA2 expression were compared. Correlation of CDCA2 expressions with patients' survival was analyzed using Kaplan-Meier method and Cox regression analysis. Results Expression of CDCA2 in PDAC cells was significantly higher than that in adjacent non-tumor tissues (U=4056.5, P<0.001). Univariate analysis showed that CDCA2 expression [hazard ratio (HR)=1.574, 95% confidence interval (CI)=1.014-2.443, P=0.043] and node metastasis (HR=1.704, 95%CI=1.183-2.454, P=0.004) were significantly associated with prognosis. Cox regression analysis showed CDCA2 expression was not an independent prognostic risk factor (HR=1.418, 95%CI=0.897-2.242, P=0.135) for PDCA patients. Stratification survival analysis demonstrated CDCA2 expression as an independent prognostic risk factor in male patients (HR=2.554, 95%CI=1.446-4.511, P=0.003) or in non-perineural invasion patients (HR=2.290, 95%CI=1.146-4.577, P=0.012). Conclusions CDCA2 is highly expressed in PDAC tumor tissue. Although CDCA2 is not an independent prognostic risk factor for PDAC patients, it might be used to help predict prognosis of male or non-perineural invasion patients of PDAC.

Glucose-regulated protein 78 (GRP78) is a member of the heat-shock protein 70 family. We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma (PDAC) patients. The associations between the expression levels of GRP78, clinicopathological factors, and overall survival were evaluated. The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues (p < 0.05). The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage (p < 0.05) and a shorter overall survival (OS, p < 0.05). In an in vitro study, the regulation of GRP78 in the PDAC cell lines affected the proliferation, migration, and invasion of PDAC cells through the regulation of CyclinD1, cyclin-dependent kinase (CDK) 4, CDK6, phospho-signal transducer, activator of transcription 3 (p-STAT3), janus kinase 2 (JAK2), ras homolog gene family member A (RhoA), Rho-associated kinase 1 (ROCK1), and sterile alpha motif domain containing protein 4 (Smad4). The present data suggest that GRP78 plays a crucial role in the proliferation, migration, and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most highly malignant tumors with a very poor prognosis. In addition to the cancer cells, the stroma of tumor can expand by 50% and influence cancer cell growth. Cancer-associated fibroblasts (CAFs) are important components of tumor stroma. Cancer cells, normal fibroblasts, normal epithelial cells as well as bone marrow-derived myofibroblasts contribute to the emergence of CAFs through various cytokines (e.g., TGF-β, SHH, PDGF) and epithelial-to-mesenchymal transition. CAFs affect cancer growth, survival, metastasis, angiogenesis and immunosurveillance through the secretion of various cytokines, such as CXCL12 and secreted protein acidic and rich in cystein. Also, CAFs correlate to the prognosis and chemoresistance of PDAC patients. As novel therapeutic targets, CAFs, and their relative factors, represent an important role in PDAC therapy.

Background: The cytokine interleukin-22 (IL-22) and its receptor are present in the tumor microenvironment. Their function in pancreatic ductal adenocarcinoma (PDAC) remains largely unknown. The goal of the present study was to measure the expression of IL-22 and IL-22R in PDAC and assess their relationship with clinicopathological features and prognosis., Methods: The expression of IL-22 and IL-22R was evaluated by immunohistochemistry in PDAC tissues from 57 patients and by Western blotting in six tumors and adjacent nontumor tissues. A statistical analysis was conducted to assess the relationship between levels of expression, clinicopathological factors, and overall survival. In addition, the relationship between the expression of IL-22 and IL-22R and invasion was assessed by Western blotting and transwell assay with the PDAC cell lines PANC1 and BxPC3., Results: Positive IL-22 staining was detected in PDAC tissues and adjacent nontumor tissues. Positive IL-22R staining was detected in PDAC cells. High expression of IL-22 and IL-22R correlated significantly with lymph node involvement. IL-22 increased the phosphorylation of signal transducer and activator of transcription3, the expression of matrix metalloproteinase 9, and the invasion in PANC1 and BxPC3 cells in vitro while silencing of IL-22R RNA caused opposite effects. Most importantly, overall survival was significantly poorer in patients with high expression of IL-22 and IL-22R than in those with low expression., Conclusions: These findings reveal the positive role of IL-22 and IL-22R in invasion and metastasis in human PDAC. IL-22 and IL-22R may be suitable independent prognostic markers in PDAC.

Background: Chemoresistance is an important clinical problem in pancreatic cancer. As the mitogen-activated protein kinases (MAPKs) have been found to be involved in the development of chemoresistance in a variety of cancer cell lines, the aim of the current study was to assess the role and mechanism of MAPK signaling in mediating chemoresistance in pancreatic cancer cells., Materials and Methods: The effects of pharmacological inhibition of MAPKs on resistance of pancreatic cancer cells to apoptosis induced by treatment with chemotherapeutic drugs were analyzed., Results: Compared with parental cells, the activity of extracellular signal-regulated kinase (ERK) was elevated in all of the three chemoresistant sublines at basal conditions. Inhibition of the ERK pathway by PD98059 sensitized cells to 5-fluorouracil (5-FU), whereas cells became more resistant to Adriamycin (ADM; Meiji Seika, Tokyo, Japan) and gemcitabine (GEM). 5-FU induced apoptosis primarily via a caspase-8-dependent pathway, and ADM and GEM via caspase-9. PD98059 enhanced the activity of caspase-8 and inhibited the activation of caspase-9. In addition, PD98059 regulated the level of phospho-Bcl-2., Conclusions: These data suggest that although constitutive activation of the ERK pathway might be a marker of chemoresistance, the effects of this pathway on chemoresistance of pancreatic cancer cells are drug dependent. This study also provides evidence for a possible link between the ERK pathway and activation of the caspases and Bcl-2.