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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Pancreatic ductal adenocarcinoma (PDAC) remains a refractory disease. Programmed cell death protein-1 (PD-1) monotherapy has shown strong performance in targeting several malignancies. However, the effect and mechanism of intrinsic PD-1 in pancreatic cancer cells is still unknown. In this study, associations between clinicopathological characteristics and stained tissue microarrays of PDAC specimens were analyzed along with profiling and functional analyses. The results showed that cell-intrinsic PD-1 was significantly correlated with overall survival (OS). Independently of adaptive immunity, intrinsic PD-1 promoted tumor growth in PDAC. Concomitantly, the overexpression of intrinsic PD-1 enhanced cancer proliferation and inhibited cell apoptosis in vitro and in vivo. Mechanistically, PD-1 binds to the downstream MOB1, thereby inhibiting its phosphorylation. Moreover, greater synergistic tumor suppression in vitro resulted from combining Hippo inhibitors with anti-PD-1 treatment compared with the suppression achieved by either single agent alone. Additionally, Hippo downstream targets, CYR61 (CCN1) and CTGF (CCN2), were directly affected by PD-1 mediated Hippo signaling activation in concert with survival outcomes. Finally, the formulated nomogram showed superior predictive accuracy for OS in comparison with the TNM stage alone. Therefore, PD-1 immunotherapy in combination with Hippo pathway inhibitors may optimize the anti-tumor efficacy in PDAC patients via targeting cell-intrinsic PD-1., (Published by Elsevier B.V.)

Background and Objectives: The Sendai consensus guidelines (SCG) and Fukuoka consensus guidelines (FCG) have been examined for their roles in predicting advanced neoplasia (AN) in pancreatic cystic neoplasm (PCN) patients with mixed results. We aim to evaluate the utilities of both guidelines in a Chinese cohort with preoperatively diagnosed mucinous PCNs., Methods: One hundred ninety-seven patients who underwent resections from 2008 to 2015 in Zhong Shan Hospital, Fudan University for suspected PCNs were retrospectively reviewed. Receiver operating characteristic (ROC) curves were calculated and compared to measure diagnostic value., Results: Fifty-five patients were diagnosed with AN pathologically. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the SCG high-risk (SCG HR ) criteria were 87.3%, 28.2%, 32.0%, 85.1%, and 44.7%, respectively, and for the FCG high-risk (FCG HR ) criteria, they were 40.0%, 95.8%, 78.6%, 80.5%, and 80.2%, respectively. ROC curve comparison analyses showed that the FCG HR were superior to the SCG HR (P = 0.02). The performance of the FCG HR was enhanced with CA19-9 incorporated (P = 0.004)., Conclusions: The FCG were superior to the SCG in this retrospective analysis, which could be further improved by the incorporation of CA19-9. However, the practical safety remains uncertain because of missed invasive carcinoma cases., (© 2017 Wiley Periodicals, Inc.)

We sought to retrospectively analyze the outcomes of patients with intraductal papillary mucinous neoplasm (IPMN) at our pancreatic surgery center, and to evaluate the prognostic value of histological subtype.The clinical data of 121 IPMNs treated in our center between 2005 and 2014 were retrospectively analyzed. Pathological slides were thoroughly reviewed by 2 specialized pathologists.Of the 121 patients, 48, 57, and 16 had main-duct, branch-duct, and mixed type IPMNs, respectively. Forty-one patients had invasive IPMNs. Histological subtypes consisted of 35 intestinal (28.9%), 56 gastric (46.3%), 29 pancreatobiliary (24.0%), and 1 oncocytic type (0.8%). Histological subtype was associated with radiological type, T stage, and degree of dysplasia (P < .05). No significant difference in overall survival was observed among the 4 histological subtypes, regardless of whether we considered all IPMNs (P = .106), or invasive IPMNs only (P = .828). However, the overall survival was associated with radiological type, T stage, degree of dysplasia, lymph-node status, and nerve invasion. For invasive IPMNs, the overall survival was associated with nerve invasion and lymph-node status; however, the association between nerve invasion and overall survival lost statistical significance after multivariate analysis.Histological subtype had limited prognostic value in patients with IPMNs, and the main prognostic factor for patients with invasive IPMNs was the lymph-node status.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. Recent studies have focused on the role of lymphocytes in the PDAC microenvironment. Using immunohistochemistry, our study explored the clinical significance of intratumoral or peritumoral CD4(+)Foxp3(+) regulatory T cells (Tregs) and CD8(+) T cells in the tumor microenvironment and analyzed their relation to the prognosis of PDAC in a consecutive series of 92 patients after resection. CD8(+) T cells were more frequently seen within peritumoral sites, while CD4(+)Foxp3(+) Tregs were more frequent within intratumoral areas. Neither exhibited any relationship with other clinicopathologic factors. Patients with low levels of intratumoral Tregs had longer disease-free survival than those with higher levels (DFS 22.2 vs. 11.2 months, p < 0.001), and patients with higher levels of peritumoral CD8(+) T cells had longer overall survival than those with lower levels (OS 31.0 vs. 14.2 months, p < 0.001). Multivariate analysis demonstrated that intratumoral Tregs (hazard ratio, HR 3.39, p = 0.010) and peritumoral CD8(+) T cells (HR 0.10, p < 0.001) are related to DFS and OS, respectively. These results indicate that intratumoral Tregs are a negative predictor of DFS, while peritumoral CD8(+) T cells are a positive predictor of OS for PDAC patients with pancreatectomy.