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Objective: Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains uncertain., Methods: Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy (GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated., Results: The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than ≤ 30% had significantly shorter 5-year overall survival (OS) and recurrence-free survival (RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-node-metastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS., Conclusions: Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC., Competing Interests: No potential conflicts of interest are disclosed., (Copyright: © 2024, The Authors.)

Purpose: Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA, pancreatic ductal adenocarcinoma). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1α (HIF-1α) and its mechanistic roles underlying PDA response to oxygen and glucose restrains., Experimental Design: Gene expression and its association with clinicopathologic characteristics of patients with PDA and mouse models were analyzed using IHC. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-immunoprecipitation, and dual luciferase reporter., Results: There was concomitant overexpression of both GRP78 and HIF-1α in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1α, particularly colocalization in nucleus. Induction of HIF-1α expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1α and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1α protein complexes to the promoters of HIF-1α and LDHA genes and transactivation of their transcriptional activity., Conclusions: Protein complex of GRP78 and HIF-1α directly binds to HIF-1α own promoter and LDHA promoter, enhances the transcription of both HIF-1α and LDHA, whereas glucose deprivation increases GRP78 expression and further enhances HIF-1α and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance., (©2023 American Association for Cancer Research.)

Background: A survival benefit has been seen for both adjuvant nab-paclitaxel plus gemcitabine (AG) and S-1 chemotherapy compared to gemcitabine (GEM) for resectable pancreatic cancer in the APACT (2019) and JASPAC01 trials (2016), respectively. However, supporting evidence regarding the effectiveness of AG or S-1 compared to gemcitabine in real-world clinical practice remains lacking., Methods: Our study included all 246 pancreatic cancer patients who underwent surgical treatment and received postoperative adjuvant chemotherapy with AG, S-1, or GEM except for those meeting exclusion criteria (R2 resection, neoadjuvant therapy, or synchronous malignancy) at Tianjin Medical University Cancer Institute and Hospital from June 2015 to July 2021. The primary outcome was overall survival (OS) and recurrence-free survival (RFS)., Results: In total, 246 patients were included, of whom 54(22%) received adjuvant AG, 103(41%) received adjuvant S-1, and 89(37%) received adjuvant GEM. Adjuvant S-1 was associated with a prolonged OS compared to GEM (median OS S-1 vs GEM: 27.0 vs 20.0 months; HR: 0.65, P = .016) and a significantly prolonged RFS compared to GEM (median RFS S-1 vs GEM: 20.0 vs 8.2 months; HR: 0.58, P = .002). After adjusting for known prognostic factors in multivariate Cox regression analysis, this survival benefit persists and is consistent in most subgroups in our subgroup analysis. However, no statistically significant differences in OS or RFS were seen between patients treated with AG and patients treated with GEM., Conclusions: In this retrospective real-world study, adjuvant S-1 chemotherapy was associated with improved survival compared to GEM while no differences in OS or RFS were observed for AG compared to GEM., 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 © 2023 Li, Guo, Sun, Lu, Chang, Wang, Gao, Gao and Zhao.)

Tumor deposits (TDs) are associated with poor prognosis in several malignancies and have been incorporated into the tumor-node-metastasis (TNM) staging system for colorectal cancer. This study aims to explore the significance of TDs in pancreatic ductal adenocarcinoma (PDAC). All patients who underwent pancreatectomy with a curative intent for PDAC were retrospectively enrolled. Patients were categorized into 2 groups according to the status of TDs: the positive group, in which TDs were present, and the negative group, in which TDs were absent. The prognostic significance of TDs was evaluated. In addition, a modified staging system was developed by incorporating TDs into the eighth edition of the TNM staging system. One hundred nine (17.8%) patients had TDs. Patients with TDs demonstrated significantly lower 5-year overall survival (OS) and recurrence-free survival (RFS) rates than those without TDs (OS: 9.1% vs. 21.5%, P =0.001; RFS: 6.1% vs. 16.7%, P <0.001). Even after matching, patients with TDs still had significantly worse OS and RFS than those without TDs. In the multivariate analysis, the presence of TDs was an independent prognostic factor in patients with PDAC. The survival of patients with TDs was similar to that of patients with N2 stage disease. The modified staging system had a greater Harrell's C-index than the TNM staging system, which indicates better performance in predicting survival. The presence of TDs was an independent prognostic factor for PDAC. Categorizing patients with TDs into N2 stage improved the accuracy of the TNM staging system in predicting prognosis., Competing Interests: None., (AJCR Copyright © 2023.)