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Panja S, Kapoor E, Siddhanta K, Jogdeo CM, Sil D, Khan RI, Kumari N, Ding L, Gendelman HE, Singh AB, Oupický D. Bioactive polymers as stimulus-responsive anti-metastatic combination agents to treat pancreatic cancer. Biomaterials 2025; 320:123255. [PMID: 40107179 DOI: 10.1016/j.biomaterials.2025.123255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
The intractable and devastating nature of pancreatic ductal adenocarcinoma (PDAC) necessitates an urgent need for novel therapies. This study presents the development of a novel polymer prodrug system for the combination treatment of PDAC, based on an optimized pharmacologically active anti-metastatic macromolecular carrier, PCQ, conjugated with gemcitabine (GEM). Structure-activity relationship evaluations showed that random PCQ copolymers exhibited superior anti-migratory activity compared to the gradient PCQ analogs. GEM was incorporated into the random PCQ copolymers using disulfide linker to prepare a reduction-responsive prodrug, PCQ(r)6-SS-GEM12. The resultant therapeutic system presents a pharmacologically active delivery strategy that targets both the proliferative and the metastatic phenotype in PDAC. The PCQ(r)6-SS-GEM12 prodrug demonstrated a selective release of GEM under the reductive tumor environment leading to a significant inhibition of tumor growth with pronounced anti-metastatic effect. Collectively, our data show that the combination of anti-metastatic PCQ and cytotoxic GEM-based reduction-responsive prodrug polymer offers an innovative strategy to treat PDAC.
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Affiliation(s)
- Sudipta Panja
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA; Department of Pharmacology and Experimental Neuroscience, USA
| | - Ekta Kapoor
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Kasturi Siddhanta
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Chinmay M Jogdeo
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Diptesh Sil
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Rubayat I Khan
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Neha Kumari
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | - Ling Ding
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA
| | | | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, USA.
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Quinn PL, Saiyed S, Ejaz A. Shared-decision making in pancreatic cancer: A scoping review. PATIENT EDUCATION AND COUNSELING 2025; 137:108828. [PMID: 40383042 DOI: 10.1016/j.pec.2025.108828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 03/31/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
PURPOSE This review aimed to map the current landscape of literature on informed and shared decision-making (SDM) among patients with pancreatic cancer (PC). METHODS PubMed, Scopus, Embase, and PsycINFO were queried for studies published before January 2024 that measured SDM or evaluated interventions targeted at SDM among patients with PC. Studies were excluded if they focused on clinician decision-making or the quality of education materials. The included studies were evaluated for interventions, assessment type, and key findings. RESULTS Our initial search identified 1194 studies, with 16 studies meeting our inclusion criteria: 4 cross-sectional, 1 mixed method, 8 qualitative, and 3 experimental. Common themes identified across studies included that there was a subset of patients that did not feel involved in their care, patients felt overwhelmed with information during the initial consultation, patients understood that there were limited treatment options, and patients did not always understand treatment decisions. The experimental studies each evaluated a different intervention (i.e., decision aid, clinician training, or combination) with mixed results. CONCLUSIONS There is limited data regarding SDM in PC, however, common themes found that PC patients commonly did not feel involved in their care. Future research should focus on role congruence in decision-making, patient empowerment, improving the delivery and comprehension of treatment information, and interventions to improve the SDM process.
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Affiliation(s)
- Patrick L Quinn
- The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | | | - Aslam Ejaz
- University of Illinois Chicago, Chicago, IL, United States.
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Yong JP, Mu XY, Zhou CF, Zhang KK, Gao JQ, Guo ZZ, Zhou SF, Ma Z. Radiofrequency ablation of liver metastases in a patient with pancreatic cancer and long-term survival: A case report. World J Clin Cases 2025; 13:100169. [DOI: 10.12998/wjcc.v13.i20.100169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/05/2024] [Accepted: 03/06/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND According to the GLOBCAN2022 database, pancreatic cancer has become the 6th leading cause of cancer-related death worldwide. The latest statistics suggest that the incidence of pancreatic cancer is increasing at a rate of 0.5% to 1.0% per year, and it is expected to become the 2nd leading cause of tumor-related deaths in the United States by 2030. More than 50% of pancreatic cancer patients have already developed distant metastases at the time of diagnosis, with the liver being the most common site. Patients with pancreatic cancer with liver metastasis (PCLM) have a worse prognosis than those with locally progressed pancreatic cancer, with a median survival of less than six months. Therefore, the outcome of liver metastases is often a vital determinant of the prognosis of patients with PCLM. There are few successful cases of localized treatment for PCLM patients. Our department recently performed local radiofrequency ablation (RFA) treatment for a PCLM patient through an evidence-based medicine approach, with remarkable therapeutic effects.
CASE SUMMARY The patient was admitted to the hospital on May 03, 2018, 3 weeks after pancreatic cancer surgery. In October 2017, the patient presented with lower back pain. No abnormalities were detected via computed tomography (CT), colonoscopy, or gastroscopy. However, on March 18, 2018, the patient was investigated in a foreign hospital via CT, which suggested occupational lesions in the descending part of the duodenum, and magnetic resonance imaging suggested pancreatic occupancy. He was considered to be suffering from pancreatic cancer. He underwent laparoscopic-assisted pancreatic + duodenum + superior mesenteric vein partial resection and reconstruction under general anesthesia on March 26, 2018 at The Affiliated Hospital of Xuzhou Medical University. The pancreas and duodenum were partially resected. Postoperative pathology showed adenocarcinoma of the pancreas (moderately differentiated), partly mucinous carcinoma, invading the mucosal layer of the duodenum; the tumor size was 4.5 cm × 4 cm × 4 cm. There was no apparent nerve or vascular invasion. There was no cancer or involvement of the pancreas section or expected hepatic duct margins. There was no cancer involvement in the gastric and duodenal sections. There was no cancer metastasis to the peripheral lymph nodes of the pancreas (0/9). No metastasis to the gastric lesser curvature or more significant curvature lymph nodes (0/1, 0/5) was detected, and the peri-intestinal lymph nodes showed no cancer metastasis (0/4). Although the gallbladder showed signs of chronic cholecystitis, there was no cancer involvement, and the lymph nodes in Groups 12 and 13 also showed no cancer metastasis (0/6, 0/1). His postoperative recovery was acceptable. CT was performed on May 2018 at our hospital and found the following: (1) Double lung bronchial vascular bundles slightly heavier than normal; (2) Postoperative changes in the pancreas and a retention tube shadow in front of the head of the pancreas; (3) Small cysts in the right lobe of the liver; (4) Abdominopelvic effusion; and (5) Para splenic enlargement. pTNM stage: PT3N0M0. The patient was in the second stage of postoperative pancreatic cancer, with a potential risk of recurrence considering the patient's postoperative body quality deviation. The patient was unable to tolerate the standard multidrug combination and underwent six cycles of single-agent gemcitabine chemotherapy from May 10, 2018 to August 31, 2018 (the specific drug dosage was 1.4 g/d1/d8 gemcitabine injection, which was repeated every 21 days). Efficacy was determined to be stable disease after 2, 4, and 6 cycles. The side effects during treatment were tolerable.
CONCLUSION This case suggests that RFA can serve as a viable local treatment modality for selected patients with PCLM, offering a chance for long-term survival. Such localized interventions, when carefully tailored, may complement systemic therapies in controlling metastatic pancreatic cancer.
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Affiliation(s)
- Jin-Peng Yong
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Xiao-Yan Mu
- Department of Oncology, Longhua Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 20001, China
| | - Chao-Feng Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Ke-Ke Zhang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Jie-Qiong Gao
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhi-Zhong Guo
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Shi-Fan Zhou
- Department of Oncology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Zhen Ma
- Department of Neurology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
- Department of Oncology, Henan Hospital of Traditional Chinese Medicine, Zhengzhou 450000, Henan Province, China
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Wang X, Gong M, Zhu Z, Zhang B, Han L, Li W, Wu Z, Ma Q, Wang Z, Qian W. Rutin protects the pancreas from inflammatory injury and oncogene-driven tumorigenesis by inhibiting acinar to ductal metaplasia. Eur J Pharmacol 2025; 998:177536. [PMID: 40120793 DOI: 10.1016/j.ejphar.2025.177536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 03/25/2025]
Abstract
Rutin is a valuable traditional Chinese medicine known for its anti-inflammatory and anticancer effects. It has been shown to be effective in treating various inflammation-associated diseases. Here, we investigated the influence of rutin on acute pancreatitis and tumorigenesis. Using C57BL/6J mice and Kras mutant transgenic mice, we induced pancreatitis and acinar regeneration models. Pancreatic malondialdehyde (MDA), superoxide dismutase (SOD) activity and reduced glutathione (GSH) contents were measured for oxidative stress. Histological staining and a pancreatic acinar 3D culture model were used to clarify the influence of rutin on ADM in vivo and in vitro. Western blotting was adopted to detect ADM markers amylase and CK19. We found that rutin ameliorated inflammatory injury to the pancreas in both caerulein- and arginine-induced AP. Then, we revealed that the anti-damage effect of rutin may be due to its inhibition of oxidative stress. In addition, an acinar 3D culture model showed that rutin inhibited the formation of ADM by activating AMPK in acinar cells. Finally, the activation of AMPK is believed to be a potential mechanism by which rutin exerts inhibitory effects on Kras-driven tumorigenesis. Rutin inhibited AP-induced pancreatic injury and oncogenic Kras-driven tumorigenesis by inhibiting ADM.
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Affiliation(s)
- Xueni Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Mengyuan Gong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zeen Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Bo Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Liang Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Wei Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Pancreatic Disease Center of Xi'an Jiaotong University, Xi'an, 710061, China.
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Shi Y, Liu J, Cheng Q, Wu S, Song W, Wang K, Chen Z, Li X, Wei Q, Tayier D, Liao B, Yang Z. METTL3/IGF2BP3 mediates ORC6 via N6-methyladenosine modification to promote the progression of pancreatic ductal adenocarcinoma. Gene 2025; 955:149468. [PMID: 40185346 DOI: 10.1016/j.gene.2025.149468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/19/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is recognized globally as one of the most lethal tumours, and effective biomarkers to diagnose PDAC early are needed. ORC6, a subunit of the origin recognition complex (ORC), initiates DNA replication and ensures genomic stability. Previous studies have indicated that ORC6 is procarcinogenic in various cancers, yet its role in PDAC remains uninvestigated. METHODS We evaluated the relationships between ORC6 expression and the clinical features of patients with PDAC with the TCGA, GTEx, and GEO databases. The role of ORC6 in PDAC cells was explored by RNA interference in vitro and in vivo. Next, we verified the effect of the METTL3/IGF2BP3/ORC6 axis on PDAC progression by western blotting, RT-qPCR, RNA immunoprecipitation, and methylated RNA immunoprecipitation. Finally, transcriptome analysis was performed to explore the influence of ORC6 on p53 in PDAC cells. RESULTS Elevated ORC6 levels were observed in PDAC cells, which correlated with poorer clinical outcomes. Both in vivo and in vitro experiments demonstrated that ORC6 knockdown suppressed proliferation and promoted apoptosis. Additionally, we demonstrated that METTL3/IGF2BP3 interacted with ORC6 mRNA via N6-methyladenosine modification to improve ORC6 mRNA stability. Transcriptomic analysis and experiments indicated that ORC6 promoted PDAC progression by inhibiting serine-15 phosphorylation in p53. CONCLUSION Our findings validate the role of ORC6 in PDAC and support the hypothesis that the METTL3/IGF2BP3/ORC6/p53 axis may be a novel therapeutic target for PDAC, and inhibiting this axis may be an advantageous therapeutic strategy for curing PDAC.
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Affiliation(s)
- Yang Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Junwei Liu
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China
| | - Qian Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Shuaihui Wu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Wenjing Song
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Kunlei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Zhinan Chen
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Xinyin Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Qifeng Wei
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Dilinigeer Tayier
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Bo Liao
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China.
| | - Zhiyong Yang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China.
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Xiao L, Hu R, Chen W, Gao J, Zhao Y, Wang Z, Du G, Tian Y, Lai L, Liu L, Su M. An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity. Neoplasia 2025; 65:101161. [PMID: 40262436 PMCID: PMC12053764 DOI: 10.1016/j.neo.2025.101161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/14/2025] [Accepted: 03/14/2025] [Indexed: 04/24/2025]
Abstract
Tumors exploit immune checkpoints to evade immune responses. Therefore, targeting these checkpoints has become a key strategy in cancer immunotherapy. In this study, we have developed a novel immune checkpoint inhibitor (ICI) targeting the B7 family-related molecule BTN2A2. The human BTN2A2 protein, which was highly expressed in some tumor tissues and activated antigen-presenting cells (APCs), can inhibit T cell activation and proliferation. The anti-BTN2A2 monoclonal antibody (mAb) can neutralize the inhibitory effect of BTN2A2 on T cells. In mouse models of pancreatic cancer and glioma, compared to the control group, the anti-BTN2A2 treatment group exhibited tumor shrinkage of 35.8 % (P < 0.05) and 51.2 % (P < 0.01), respectively, along with increased CD8+ tumor-infiltrating lymphocytes (TILs) by 1.7-fold (P < 0.001) and 2.2-fold (P < 0.001), respectively. In addition, anti-BTN2A2 mAb also increased the infiltration of B cells, M1 macrophages, and the expression of inflammatory cytokines in T cells, while reducing the infiltration of M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Thus, anti-hBTN2A2 mAb normalizes the immunodeficient tumor microenvironment (TME) and inhibits tumor growth. Our results suggest that targeting the BTN2A2 immune checkpoint may represent a novel strategy for cancer treatment, especially in immunosuppressive 'cold' tumors.
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Affiliation(s)
- Li Xiao
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Rong Hu
- Translotional Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Wei Chen
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Jie Gao
- Translotional Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Youbo Zhao
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Guizhou Province Key Laboratory of Regenerative Medicine, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Zuli Wang
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Guizhou Province Key Laboratory of Regenerative Medicine, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Guangshi Du
- Translotional Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Yishen Tian
- Translotional Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113
| | - Laijun Lai
- Department of Allied Health Sciences, University of Connecticut, 1390 Storrs Road, Storrs, CT, 06269, USA
| | - Lu Liu
- The Public Health Clinical Center of Guiyang City, 6 Daying Road, Guiyang City, Guizhou, China, 550004
| | - Min Su
- National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113; Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, China, 561113.
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Dong X, Wu L, Gong L, Huang D, Guo J, Ma M, Xiao L, Xu S, Chang J, Che X, Hang J. PPP3CB inhibits pancreatic cancer progression by promoting ATOH8 translocation and transcriptionally regulating Sp1. Life Sci 2025; 372:123631. [PMID: 40222712 DOI: 10.1016/j.lfs.2025.123631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 04/06/2025] [Accepted: 04/08/2025] [Indexed: 04/15/2025]
Abstract
AIMS Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy which lacks effective therapeutic targets. We previously demonstrated that low PPP3CB expression correlates with poor prognosis in PDAC. This study aims to investigate the function and underlying mechanism of PPP3CB in pancreatic cancer progression. MATERIALS AND METHODS We analyzed PPP3CB expression via immunohistochemistry in PDAC specimens and investigated its prognostic value by statistical method. Differentially expressed genes were analyzed by qRT-PCR and Western blot. Mass spectrometry, Co-IP, ChIP-seq, luciferase analysis, flow cytometry, immunofluorescence and confocal microscopy were performed to investigate the underlying mechanisms of PPP3CB and regulation of ATOH8/Sp1 axis. Mice xenograft models were employed to assess the malignant behaviors in vivo. KEY FINDINGS We found that PPP3CB expression was higher in patients with early-stage PDAC than in those with late-stage PDAC. PPP3CB overexpression impaired PDAC proliferation and metastasis in vitro and in vivo, whereas its depletion or treatment with CsA-a PPP3CB inhibitor, had the opposite effect. Liquid chromatography-tandem mass spectrometry predicted an interaction between PPP3CB and ATOH8. Further investigation confirmed that PPP3CB interacts with ATOH8 and enhances its nuclear translocation in PDAC cells. ChIP-seq and luciferase analyses showed that ATOH8 binds to the promoter of Sp1, a well-known oncogenic transcription factor in PDAC. Furthermore, PPP3CB transcriptionally inhibits Sp1 expression and suppresses pancreatic cancer metastases by increasing ATOH8 nuclear content. SIGNIFICANCE These findings suggest a novel role for PPP3CB in preventing PDAC progression by promoting ATOH8 nuclear translocation and transcriptionally inhibiting Sp1. Consequently, PPP3CB emerges as a potential therapeutic target for PDAC.
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Affiliation(s)
- Xiao Dong
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Lixia Wu
- Department of Oncology, Shanghai JingAn District ZhaBei Central Hospital, Shanghai 200070, China
| | - Libao Gong
- Department of Oncology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Daijia Huang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Jinfeng Guo
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Meng Ma
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Li Xiao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Shuangwei Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianhua Chang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
| | - Xu Che
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
| | - Junjie Hang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
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8
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Ji W, Xiong Y, Yang W, Shao Z, Guo X, Jin G, Su J, Zhou M. Transcriptomic profiling of blood platelets identifies a diagnostic signature for pancreatic cancer. Br J Cancer 2025; 132:937-946. [PMID: 40133510 DOI: 10.1038/s41416-025-02980-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 02/26/2025] [Accepted: 03/10/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PaCa) is a deadly malignancy that is often diagnosed at an advanced stage, limiting treatment and reducing survival. There is an urgent need for convenient and accurate diagnostic markers for the early detection of PaCa. METHODS In this multicenter case-control study, we performed transcriptome analysis of 673 platelet samples from different in-house and public cohorts. RNA sequencing and RT-qPCR were used to discover and validate potential platelet biomarkers. A multi-gene signature was developed using binomial generalized linear model and independently validated in multicenter cohorts. RESULTS Two platelet RNAs, SCN1B and MAGOHB, consistently showed robust altered expression patterns between PaCa and healthy controls across cohorts, as confirmed by both RNA sequencing and RT-qPCR. The diagnostic two-RNA signature, PLA2Sig, demonstrated remarkable performance in detecting PaCa, with area under the receiver operating characteristic curve (AUC) values of 0.808, 0.900, 0.783, and 0.830 across multicenter cohorts. Furthermore, PLA2Sig effectively identified resectable stage I&II PaCa cases with an AUC of 0.812. Notably, PLA2Sig outperformed the traditional serum markers carcinoembryonic antigen and carbohydrate antigen 19-9 in distinguishing PaCa from healthy controls, and is complementary to established blood-based screening biomarkers. CONCLUSION These findings provide preliminary but promising evidence for the potential utility of platelet RNAs as an alternative non-invasive liquid biopsy tool for the early detection of PaCa.
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Affiliation(s)
- Weiping Ji
- Department of General Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
- Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yichun Xiong
- Department of General Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Wei Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230001, China
| | - Zhuo Shao
- Department of General Surgery, Shanghai Changhai Hospital of Navy Medical University, Shanghai, 200438, China
| | - Xiaoling Guo
- Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Gang Jin
- Department of General Surgery, Shanghai Changhai Hospital of Navy Medical University, Shanghai, 200438, China
| | - Jianzhong Su
- Department of General Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
| | - Meng Zhou
- Department of General Surgery, School of Biomedical Engineering, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
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9
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Chuong MD, Ashman J, Jethwa K, Kharofa J, Kim H, Koay E, Ludmir E, Miller E, Nelson B, Reyngold M, Sanford N, Chang D. Moving From the Background Toward the Spotlight: A Critical Review of Radiation Therapy for Locally Advanced Pancreas Cancer. Int J Radiat Oncol Biol Phys 2025; 122:294-312. [PMID: 40032056 DOI: 10.1016/j.ijrobp.2025.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/31/2025] [Accepted: 02/16/2025] [Indexed: 03/05/2025]
Abstract
Radiation therapy (RT) for locally advanced pancreatic cancer (LAPC) continues to be controversial. Advances in both systemic therapy and RT techniques have changed the landscape of LAPC management in recent years. Clinical outcomes of ablative RT have been encouraging, and randomized clinical trials may clarify the role of RT for LAPC. We present a contemporary critical review of key aspects regarding optimal patient selection, radiation dose escalation techniques, novel radiosensitizers and radioprotectors, and treatment response assessment for LAPC.
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Affiliation(s)
- Michael D Chuong
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida.
| | - Jonathan Ashman
- Department of Radiation Oncology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Krishan Jethwa
- Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, Minnesota
| | - Jordan Kharofa
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Hyun Kim
- Department of Radiation Oncology, Washington University in St. Louis, Missouri.
| | - Eugene Koay
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ethan Ludmir
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric Miller
- Department of Radiation Oncology, Ohio State University, Columbus, Ohio
| | - Bailey Nelson
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Marsha Reyngold
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nina Sanford
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Daniel Chang
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
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10
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Xu Y, Shi Y, Jiang T, Wu Q, Lang R, Wang Y, Yang M. Radiomics-based histological grading of pancreatic ductal adenocarcinoma using 18F-FDG PET/CT: A two-center study. Eur J Radiol 2025; 187:112070. [PMID: 40187196 DOI: 10.1016/j.ejrad.2025.112070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/05/2025] [Accepted: 03/24/2025] [Indexed: 04/07/2025]
Abstract
OBJECTIVE To explore the value of radiomics features derived from 18F-FDG PET/CT images in predicting the histological grade of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS A retrospective analysis was conducted using data from patients with suspected pancreatic cancer, who histologically confirmed as PDAC within 14 days after 18F-FDG PET/CT scan in one of two hospitals. Tumors were divided into high-grade (undifferentiated or poorly differentiated), and low-grade (moderately or well differentiated). Two researchers independently used uRP to perform layer-by-layer tumor segmentation in both PET and CT images of each patient, and extract features. Model performance was evaluated using 5-fold cross-validation on the entire multi-center cohort, with results averaged across all folds. The least absolute shrinkage and selection was used for feature selection, and support vector machine (SVM), random forest (RF), and logistic regression (LR) were employed to distinguish the grade of PDAC. The performance of the model was evaluated using the receiver operating characteristic curve. RESULTS This study comprised 111 patients (72 males and 39 females), comprising 52 patients with high-grade PDAC tumors and 59 patients with low-grade. A series of models were established by SVM, LR, and RF algorithms based on selected features. In the test set, the mean areas under the curve (AUCs) for PET image-based models using SVM, LR, and RF algorithms were 0.773, 0.772, and 0.760. For CT-based models, the mean AUCs were 0.764, 0.770, and 0.576. For PET/CT-based models, the mean AUCs were 0.840, 0.844, and 0.773. CONCLUSION Despite the lack of external validation, the PET/CT-derived radiomics model enables accurate preoperative histological grading of PDAC, offering a clinically actionable tool to neoadjuvant therapy stratification and further guide personalized medical decision-making.
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Affiliation(s)
- Yang Xu
- Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yunmei Shi
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu, China
| | - Tao Jiang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Qingxia Wu
- Beijing United Imaging Research Institute of Intelligent Imaging, Beijing, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yuetao Wang
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu, China.
| | - Minfu Yang
- Department of Nuclear Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
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11
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Ghosn B, Baniasadi MM, Jalalzadeh M, Esmaillzadeh A. Total, unprocessed, and processed red meat intake in relation to the risk of pancreatic cancer: A systematic review and dose-response meta-analysis of prospective cohort studies. Clin Nutr ESPEN 2025; 67:265-275. [PMID: 40118182 DOI: 10.1016/j.clnesp.2025.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 02/19/2025] [Accepted: 03/12/2025] [Indexed: 03/23/2025]
Abstract
Data on the association between red meat from both processed and unprocessed sources and risk of pancreatic cancer is controversial. Therefore, this study summarized current evidence on the relationship between red and processed red meat intake and pancreatic cancer risk through a meta-analysis. A systematic search was conducted on PubMed, ISI Web of Science and Scopus for prospective cohorts up to October 2024. Hazard ratio (HR) and 95 % confidence intervals (CIs) for the highest vs. the lowest category of the exposures were combined using random-effects models. Dose-response relations were explored by one-stage weighted mixed effects meta-analysis. 19 studies involving 4,291,065 participants with 13,820 pancreatic cancer cases were included. The highest intake of total red meat was positively related to risk of pancreatic cancer (Pooled HR: 1.12, 95%CIs: 1.01, 1.24; I2: 36.5 %, PQ-test: 0.10). Such association was not significant for unprocessed (Pooled HR: 1.05, 95%CIs: 0.88, 1.24; I2: 66.6 %, PQ-test: 0.002) and processed (Pooled HR: 1.02, 95%CIs: 0.86, 1.21; I2: 66.0 %, PQ-test: 0.001) red meat intake. No significant association was observed between each 3 serving/wk of total, unprocessed, and processed red meat and risk of pancreatic cancer. Also, no evidence for a nonlinear association was found for all associations. This meta-analysis suggests a positive relation between the highest consumption of total red meat and pancreatic cancer. However, this relation was not substantial in terms of unprocessed and processed red meat.
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Affiliation(s)
- Batoul Ghosn
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Moradi Baniasadi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Moharam Jalalzadeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Esmaillzadeh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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12
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Wang M, Bu H, Luo W, Zeng X, Chen G, He Y, Cao D. CA19-9, CEA and PIVKA-Ⅱ as a novel panel of serum markers for diagnosis of pancreatic cancer. Clin Biochem 2025; 137:110902. [PMID: 40024361 DOI: 10.1016/j.clinbiochem.2025.110902] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
AIM This retrospective study was aimed to evaluate the diagnostic value of a combination of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-II) in pancreatic cancer. METHODS Clinical data were collected from 111 pancreatic cancer patients and 158 patients with benign pancreatic diseases (BPD). Serum CA19-9, CEA and PIVKA-II were subjected to receiver operating characteristic curve (ROC) analysis alone and in combination for the diagnosis of pancreatic cancer. RESULTS Serum CA19-9, CEA, and PIVKA-II were higher in pancreatic cancer patients than in BPD patients (P < 0.001). ROC analysis indicated that the cutoff values were 99.390 for CA19-9, 3.065 for CEA, and 42.965 for PIVKA-II, at which the positive rate in pancreatic cancer was 78.38 % for CA19-9, 43.24 % for CEA and 48.65 % for PIVKA-Ⅱ. When serum CA19-9, CEA, and PIVKA-II were used alone, the areas under the curves (AUC), sensitivity and specificity were 0.821, 68.47 % and 89.24 % for CA19-9, 0.763, 61.26 % and 85.44 % for CEA, and 0.681, 45.95 % and 87.34 % for PIVKA-II. When serum CA19-9, CEA, and PIVKA-II were used in combination, the positivity rate was 94.59 % in pancreatic cancer with AUC of 0.903, sensitivity of 81.10 % and specificity of 88.00 %. CONCLUSION PIVKA-II is a potential serum marker of pancreatic cancer and the combination of CA19-9, CEA, and PIVKA-II is a novel panel of serum markers with promising diagnostic value for pancreatic cancer.
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Affiliation(s)
- Meifang Wang
- Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hongying Bu
- School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Weijia Luo
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xi Zeng
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Guodong Chen
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Yingchun He
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha 410208, China.
| | - Deliang Cao
- Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China; School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China; Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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13
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Fu Y, Chen L, Lv N, Wang J, Yu S, Fang Q, Xin W. miR-135b-5p/PDE3B Axis Regulates Gemcitabine Resistance in Pancreatic Cancer Through Epithelial-Mesenchymal Transition. Mol Carcinog 2025; 64:1119-1130. [PMID: 40170518 DOI: 10.1002/mc.23914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 03/11/2025] [Accepted: 03/18/2025] [Indexed: 04/03/2025]
Abstract
Gemcitabine-based chemotherapy is an effective treatment for pancreatic cancer (PC), but gemcitabine resistance frequently compromises the therapeutic efficacy, resulting in clinical chemotherapeutic failure and a poor prognosis for patients. In this study, we investigated the mechanisms of gemcitabine chemoresistance in PC by examining the roles of microRNAs linked to gemcitabine resistance and their downstream signaling pathways. In vitro experiments were performed to alter miR-135b-5p levels in PC parental and drug-resistant cells to probe its function. miR-135b-5p targets PDE3B was confirmed by using RNA-seq technology to screen for gemcitabine-resistance-associated mRNAs in PC. A series of rescue experiments were performed after cotransfection, demonstrating that PDE3B could reverse miR-135b-5p-mediated chemoresistance and epithelial-mesenchymal transition (EMT). These findings indicate that the miR-135b-5p/PDE3B axis generates resistance by stimulating the EMT signaling pathway, which provides new insights into gemcitabine chemoresistance in PC.
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Affiliation(s)
- Yuxuan Fu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Liangsheng Chen
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Neng Lv
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jia Wang
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Shuwei Yu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Qilu Fang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Wenxiu Xin
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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14
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Wang F, Xu X, Xu J, Li F, Zhang H, Wang L, Yu D. Exploring the value of multiparametric quantitative MRI in the assessment of pancreatic ductal adenocarcinoma fibrosis grading. Eur Radiol 2025; 35:3625-3637. [PMID: 39699670 DOI: 10.1007/s00330-024-11246-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/29/2024] [Accepted: 10/28/2024] [Indexed: 12/20/2024]
Abstract
OBJECTIVES To analyze the performance of multiparametric magnetic resonance imaging (MRI) in quantification of pancreatic ductal adenocarcinoma (PDAC) fibrosis grading. METHOD This prospective study enrolled 79 patients with PDAC confirmed by pathology. Multiparametric MRI including native T1 mapping, intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), diffusion kurtosis imaging diffusion-weighted imaging (DKI-DWI), and enhanced T1 mapping were performed before surgery. Masson staining was used to evaluate intratumoral fibrosis content and classified into low- and high-fibrosis groups. MRI parameters were compared between the two groups using multivariable logistic regression analysis. The correlations between fibrosis content and MRI parameters were evaluated using Pearson's correlation. RESULTS D, f, mean diffusion (MD), and enhanced T1 mapping were lower in the high-fibrosis group than in the low-fibrosis group (p < 0.001, p < 0.001, p < 0.001, p = 0.026, respectively). Native T1 mapping and extracellular volume (ECV) were opposite (All p < 0.001). No significant differences in the rest. Multivariable logistic regression revealed that native T1 mapping, MD, and ECV were independent discriminators for PDAC fibrosis grading (p = 0.037, p = 0.031, p = 0.014, respectively); the area under the curve (AUC) of native T1 mapping, MD and ECV was 0.863, 0.798, and 0.929. Among them, ECV had an extremely strong positive correlation with intratumoral fibrosis content. Native T1 mapping and MD were correlated strongly with fibrosis content (positive and negative, respectively). CONCLUSIONS ECV had the highest assessing performance for grading fibrosis in PDAC compared to other MRI parameters, and has the potential to be an imaging biomarker for predicting the fibrosis content of PDAC. KEY POINTS Question The relationship between fibrosis grade of PDAC and quantitative MRI parameters based on T1 mapping and diffusion imaging has not been fully investigated. Findings ECV performed the best in distinguishing between fibrosis grade and increased as interstitial fibrosis increased; clinical indicators offered no added value. Clinical relevance Quantitative MRI parameters provide significant value in evaluating the fibrosis grade of PDAC, which bears significant implications for preoperative risk stratification and the selection of personalized treatment strategies for patients.
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Affiliation(s)
- Fangqing Wang
- Department of Radiology, Qilu Hospital, Shandong University, Jinan, China
| | - Xinghua Xu
- Department of Radiology, Qilu Hospital, Shandong University, Jinan, China
| | - Jianwei Xu
- Department of Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Feng Li
- Department of Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Hui Zhang
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, China
| | - Lei Wang
- Department of Surgery, Qilu Hospital, Shandong University, Jinan, China.
| | - Dexin Yu
- Department of Radiology, Qilu Hospital, Shandong University, Jinan, China.
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15
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Chan AHY, Zhao Y, Tan HL, Chua DW, Ng KYY, Lee SY, Lee JJX, Tai D, Goh BKP, Koh YX. Clinical Outcomes of Neoadjuvant Therapy Versus Upfront Surgery in Resectable Pancreatic Cancer: Systematic Review and Meta-analysis of Latest Randomized Controlled Trials. Ann Surg Oncol 2025; 32:4094-4107. [PMID: 39987384 DOI: 10.1245/s10434-024-16674-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/23/2024] [Indexed: 02/24/2025]
Abstract
BACKGROUND Survival and surgical benefits of neoadjuvant treatments (NAT) in resectable pancreatic cancer (RPC) remains unclear. The role of NAT in providing additional benefits to reduce biological aggressiveness and recurrence is worth elucidating. We assessed the latest randomized controlled trials (RCTs). METHODS A systematic review and meta-analysis was performed including trials published from inception to February 2024 to evaluate survival, surgical, and short-term oncological benefits with RCTs for RPC, comparing NAT with upfront surgery. RESULTS Eight RCTs with 982 patients were analyzed. RPC treated with NAT conferred better median disease-free survival (DFS) compared to upfront surgery (HR = 0.66, p = 0.01) with a significantly improved R0 resection (RR = 1.20, p = 0.04) and pN0 rate (RR = 1.68, p < 0.001). These benefits did not translate into overall survival benefits (HR = 0.81, p = 0.06). Postoperative major morbidity and mortality did not differ significantly between treatment approaches. No significant difference was noted in resection rate (RR = 0.95, p = 0.21). However, a significantly lower surgical exploration rate was exhibited in the NAT group (RR = 0.84, p = 0.007). CONCLUSION NAT conferred better DFS with significantly improved R0 resection rate and pN0 rate compared with upfront surgery. Our findings highlight the potential benefits of NAT in enhancing survival, surgical, and short-term oncological outcomes without increasing postoperative risks.
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Affiliation(s)
- Anna Ho Yin Chan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
| | - Yun Zhao
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Hwee Leong Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Darren Weiquan Chua
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Kennedy Yao Yi Ng
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joycelyn Jie Xin Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - David Tai
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Brian Kim Poh Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Ye Xin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore.
- Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
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16
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Patel R, Fountzilas C, Horowitz M, Schultz E, Clayback KM, Knudsen ES, Witkiewicz AK, Onel K. Pancreatic adenocarcinoma in a patient with a germline RB1 pathogenic variant. Fam Cancer 2025; 24:46. [PMID: 40418431 DOI: 10.1007/s10689-025-00475-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 05/06/2025] [Indexed: 05/27/2025]
Abstract
Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma are at high risk for developing subsequent malignant neoplasms (SMNs); indeed, these are the leading cause of death for individuals cured of their retinoblastoma. With the exception of sarcomas, typically occurring at the site of antecedent radiation therapy for the original retinoblastoma diagnosis, and melanoma, little is known of other SMNs in retinoblastoma survivors. Here, we describe a unique case of pancreatic adenocarcinoma (PDAC) in a patient with a RB1 GPV who was diagnosed with retinoblastoma as an infant. At age 57, he was diagnosed with PDAC. Sequence analysis of the PDAC revealed the acquisition of a somatic second-hit in RB1 in the PDAC. Multispectral immunofluorescence analyses of the PDAC tumor illustrated selective loss of the RB protein in the tumor that was accompanied by the continued expression of p16ink4a, encoded by the CDKN2A gene. In PDAC, CDKN2A loss is a common early event that contributes to carcinogenesis. This case may suggest that PDAC is a rare late component of RB1-associated tumor predisposition and illustrates that biallelic loss of RB1 is an alternative mechanism by which the RB1-pathway can be disrupted in PDAC independent of CDKN2A inactivation.
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Affiliation(s)
- Riya Patel
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christos Fountzilas
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michael Horowitz
- The Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Emily Schultz
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Katherine M Clayback
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Erik S Knudsen
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Agnieszka K Witkiewicz
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
| | - Kenan Onel
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Departments of Cancer Prevention and Control and Medicine, Center for Precision Oncology and Cancer Prevention, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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17
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Lin J, Li Y, Sun J. Modulating immune cells within pancreatic ductal adenocarcinoma via nanomedicine. Essays Biochem 2025:EBC20243001. [PMID: 40420798 DOI: 10.1042/ebc20243001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/28/2025] [Indexed: 05/28/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense extracellular matrix (ECM) and a uniquely immunosuppressive tumor microenvironment (TME), which together form a formidable barrier that hinders deep drug penetration, limiting the efficacy of conventional therapies and leading to poor patient outcomes. Nanocarrier technology emerges as a promising strategy to improve treatment efficacy in PDAC. Nanocarriers can not only improve drug penetration through their adjustable physicochemical properties but also effectively regulate immune cell function in pancreatic cancer TME and promote anti-tumor immune response. This mini-review discusses the effects of nanocarriers on the immune microenvironment of PDAC, analyzing their mechanisms in modulating immune cells, overcoming ECM barriers, and reshaping the TME.
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Affiliation(s)
- Junyi Lin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
| | - Ying Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
| | - Jingjing Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, U.S.A
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18
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Zheng Z, Lu Z, Yan F, Song Y. The role of novel biomarkers in the early diagnosis of pancreatic cancer: A systematic review and meta-analysis. PLoS One 2025; 20:e0322720. [PMID: 40408437 PMCID: PMC12101772 DOI: 10.1371/journal.pone.0322720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/26/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Early detection of pancreatic cancer is essential for improving survival rates. However, noninvasive diagnostic methods are lacking. Novel biomarkers, detectable through liquid biopsy, such as circulating tumor DNA (ctDNA), microRNAs (miRNAs), protein markers, and metabolites, hold promise for early diagnosis. METHODS A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted for studies published from January 2014 to May 2024. Studies were included if they evaluated novel biomarkers for early pancreatic cancer detection, reported diagnostic performance metrics (sensitivity, specificity), and had a QUADAS-2 score of ≥3. Data on study characteristics, patient demographics, biomarker types, and diagnostic performance were extracted following PRISMA guidelines. A bivariate random-effects model was used to calculate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). The area under the summary receiver operating characteristic (SROC) curve assessed overall diagnostic accuracy. The primary outcome was the diagnostic accuracy (sensitivity and specificity) of novel biomarkers in detecting early-stage pancreatic cancer. RESULTS A total of 43 studies involving 19,326 participants were included, with 2,749 patients having stage I or II pancreatic cancer. The pooled sensitivities and specificities were as follows:. miRNA Biomarkers: Sensitivity 0.88 (95% CI 0.79-0.93), Specificity 0.91 (95% CI 0.82-0.95), DOR 72.68 (95% CI 26.64-198.24), AUC 0.95. Protein Biomarkers: Sensitivity 0.79 (95% CI 0.70-0.86), Specificity 0.88 (95% CI 0.82-0.93), DOR 27.74 (95% CI 14.32-53.76), AUC 0.90. Metabolite Biomarkers: Sensitivity 0.84 (95% CI 0.73-0.92), Specificity 0.85 (95% CI 0.81-0.88), DOR 31.76 (95% CI 12.38-81.48), AUC 0.90. ctDNA Biomarkers: Sensitivity 0.65 (95% CI 0.48-0.81), Specificity 0.94 (95% CI 0.88-0.97), DOR 27.73 (95% CI 12.91-59.55), AUC 0.92. Subgroup analyses showed combining biomarkers with CA19-9 improved diagnostic accuracy. Sensitivity analyses confirmed the robustness of the findings. CONCLUSIONS Novel biomarkers, particularly miRNAs and protein markers, demonstrate high diagnostic accuracy for early pancreatic cancer detection and have potential for clinical application in improving early diagnosis and patient outcomes. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, Identifier: PROSPERO (CRD42024553633).
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Affiliation(s)
- Zeyi Zheng
- School of Traditional Chinese Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Ziyu Lu
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Fei Yan
- Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yani Song
- School of Water Resources and Hydropower Engineering, Wuhan University, Wuhan, Hubei, China
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19
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Huang Y, Yang T, Yang C, Tang B, Su B, Yang X. MiR-485-3p/MELK cascade mediates tumor progression in pancreatic cancer. Sci Rep 2025; 15:17870. [PMID: 40404813 PMCID: PMC12098867 DOI: 10.1038/s41598-025-02586-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 05/14/2025] [Indexed: 05/24/2025] Open
Abstract
Pancreatic cancer remains one of the leading causes of mortality worldwide, largely due to the limitations of current clinical strategies for its treatment. As a result, identifying genetic alterations and potential therapeutic targets could offer new opportunities for improving the diagnosis and treatment of pancreatic cancer. The identification of differentially expressed genes (DEGs) and subsequent analyses, including signaling pathway enrichment, functional classification, and protein-protein interaction (PPI) network construction, were conducted using three public datasets: GSE32676, GSE71989, and GSE16515. Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves were employed to investigate the correlation between hub genes and clinicopathological features in pancreatic cancer patients. Genetic alterations were analyzed using the CBioPortal web tool. Cell proliferation was assessed through CCK-8, colony formation, and EdU assays. Tumor migration, invasion, and angiogenesis were evaluated using transwell and tube formation assays, respectively. Protein and mRNA expression levels were measured via western blot analysis and qPCR assays. The subcutaneous xenografted nude mice models were generated to evaluate the potential effect of miR-485-3p/MELK cascade on tumor growth in vivo. Our analysis revealed that MELK expression is positively correlated with poor prognosis in patients with pancreatic cancer. The overexpression or knockdown of MELK significantly influences cell proliferation, tumor metastasis, and angiogenesis across various pancreatic cancer cell lines. Furthermore, we identified that miR-485-3p regulates MELK expression by directly targeting the MELK 3'UTR binding site in pancreatic cancer cells, which subsequently impacts tumor progression. Additionally, our findings demonstrate that the miR-485-3p/MELK cascade is closely associated with tumor progression in pancreatic cancer cells. Mechanistically, the miR-485-3p/MELK cascade promotes the phosphorylation of Akt to regulate pancreatic cancer cell progression, metastasis, and angiogenesis. Furthermore, overexpression of miR-485-3p inhibits the tumor growth induced by MELK overexpression in subcutaneous xenograft model. MiR-485-3p/MELK cascade may serve as a promising biomarker and therapeutic target for the diagnosis and treatment of pancreatic cancer.
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Affiliation(s)
- Yishan Huang
- Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, 515041, China
| | - Ting Yang
- Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, 515041, China
| | - Chen Yang
- Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, 515041, China
| | - Bo Tang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Bo Su
- Department of Cell Biology, School of Basic Medical Science, Shandong University, Jinan, 250012, China.
| | - Xiaojun Yang
- Engineering Research Center of Key Technique for Biotherapy of Guangdong Province, Shantou University Medical College, Shantou, 515041, China.
- The First Dongguan Affiliated Hospital, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, China.
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20
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Wei F, Li W, Zhou T, Feng L, Yuan X, Zhang L. FAM111B and FANCD2, a dual expression signature, defines a distinct phenotype of pancreatic cancer. Cancer Cell Int 2025; 25:185. [PMID: 40405284 PMCID: PMC12101032 DOI: 10.1186/s12935-025-03819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 05/08/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Despite various treatment strategies, the incidence and mortality of pancreatic cancer (PC) are among the highest for malignant tumors. Furthermore, there is a lack of effective molecular typing and targeted therapy to treat PC subtypes. METHODS Multiplex immunofluorescence experiments were performed to explore the roles of FAM111B, FANCD2, KRAS and TP53 in human PC tissues. Kaplan-Meier survival curves were generated and a nomogram was prepared for prognostic prediction. Protein correlations were analyzed using human PC tissues and TCGA and GEO data. Pathways analysis, immunoanalysis, and drug susceptibility analysis were performed based on information in the TCGA database. RESULTS Our results indicate that expression of FAM111B and FANCD2 is correlated in human PC tissues and comprises a dual expression signature with predictive value for the prognosis of PC. Using information in public databases, we confirmed the oncogenic relevance of FAM111B and FANCD2 in PC and identified a positive correlation between FAM111B, FANCD2, TP53 and KRAS.FAM111B and FANCD2 jointly regulate ferroptosis, mitotic nuclear division, and nuclear division pathways. Both proteins were demonstrated to be positively correlated with markers of CD4 + Th2 cells and PD-L1 in the tumor microenvironment. Furthermore, drug sensitivity analysis suggested that patients with high FAM111B or FANCD2 expression were highly sensitive to chemotherapeutic and targeted drugs, indicating that these proteins may serve as predictors of treatment efficacy. CONCLUSION Elevated dual expression of FAM111B and FANCD2 is indicative of poor prognosis, alters the immune microenvironment, and exhibits sensitivity to certain therapeutic agents. Consequently, the high FAM111B/FANCD2 expression subtype may represent a novel and distinct phenotype of PC.
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Affiliation(s)
- Fang Wei
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Wanying Li
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ting Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Lijuan Feng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Lihong Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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21
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Yang F, Xu Y, Jin C, He H, Li J, Fu D. Periarterial divestment for borderline and locally advanced pancreatic cancer: An analysis of 125 cases in a single center. Surgery 2025; 184:109412. [PMID: 40398370 DOI: 10.1016/j.surg.2025.109412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 04/04/2025] [Accepted: 04/16/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Literature on factors influencing prognosis after periarterial divestment for borderline resectable or locally advanced pancreatic ductal adenocarcinoma and preventative measures for postpancreatectomy hemorrhage is scarce. This study aimed to evaluate the efficacy of Neuro-Patch for arterial reinforcement in preventing postpancreatectomy hemorrhage and explore the oncologic outcomes of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma following periarterial divestment. METHODS We conducted a retrospective analysis of 125 patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma involving arteries who underwent periarterial divestment between January 2018 and May 2022. RESULTS Among the study cohort, 54 patients underwent pancreaticoduodenectomy, 43 had distal pancreatectomy, and 28 received total pancreatectomy, with 74 patients also undergoing combined venous resection. Periarterial divestment was performed on the hepatic artery in 47 patients, the celiac artery in 3, the superior mesenteric artery in 22, and multiple arteries in 53. Neoadjuvant chemotherapy was administered to 24% of patients, with an R0 resection rate of 33.6%. The median postoperative hospital stay was 10 days, with a 90-day mortality rate of 3.2%. Neuro-Patch was used in 51 patients, leading to a significant reduction in postpancreatectomy hemorrhage (odds ratio 0.073, 95% confidence interval 0.007-0.783, P = .031). The median overall survival was 20.6 months, with 1- and 3-year survival rates estimated at 73.2% and 22.9%, respectively. Neoadjuvant chemotherapy (hazard ratio 0.494, 95% confidence interval 0.291-0.839, P = .009) and venous invasion (hazard ratio 2.041, 95% confidence interval 1.308-3.186, P = .002) emerged as independent predictors of overall survival. CONCLUSION Neoadjuvant chemotherapy significantly enhances survival outcomes of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma undergoing periarterial divestment, and it should be regarded as a standard preoperative approach. The Neuro-Patch provides structural reinforcement to the arterial wall, potentially reducing the risk of postpancreatectomy hemorrhage. However, randomized controlled trials are necessary to substantiate its efficacy and safety.
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Affiliation(s)
- Feng Yang
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yecheng Xu
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chen Jin
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hang He
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ji Li
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
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22
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Catacalos-Goad C, Hawkins J, Krueger Q, Foret N, Grdzelishvili VZ. METTL3 depletion blocks vesicular stomatitis virus replication in pancreatic cancer cells through the establishment of an intrinsic antiviral state. J Virol 2025; 99:e0228424. [PMID: 40214229 PMCID: PMC12090749 DOI: 10.1128/jvi.02284-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/25/2025] [Indexed: 05/21/2025] Open
Abstract
Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the role of methyltransferase-like 3 (METTL3), a catalytic subunit of the cellular writer complex that is responsible for N6-methyladenosine (m6A) RNA modification, as a potential host factor of VSV replication in PDAC cells. METTL3 was previously shown to be upregulated in PDAC, where it promotes cancer cell proliferation, invasion, and chemoresistance. The impact of METTL3 on life cycles of different viruses varies depending on both the virus and the cell type. Additionally, METTL3 plays a positive role in VSV replication in non-PDAC cells via m6A modification of VSV RNAs, which attenuates innate antiviral responses. In this study, we examined the role of METTL3 in 10 different human PDAC cell lines and uncovered two distinct outcomes. METTL3 depletion did not affect VSV replication in PDAC cell lines with defective innate antiviral signaling, suggesting that METTL3 is not directly involved in VSV replication. In contrast, METTL3 depletion dramatically inhibited VSV replication in PDAC cell lines with functional antiviral signaling. We show that this result is due to the RIG-I-dependent induction of a virus-independent, intrinsic antiviral state in METTL3-depleted PDAC cells. This intrinsic antiviral state was marked by type-III (but not type I or II) interferon secretion and constitutive overexpression of antiviral sensors [RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58)], transactivators (STAT1, IRF7, and IRF9), and a diverse subset of antiviral effectors, including MX1, OAS1/2/3, and IFIT1/3.IMPORTANCEPancreatic cancer is a deadly and extremely challenging disease, making it essential to develop new treatment options and improve patient survival rates. One promising approach is the use of replication-competent "oncolytic viruses" designed to specifically target and destroy cancer cells while sparing healthy ones. To create effective oncolytic virus therapies for pancreatic cancer, it is crucial to identify host factors that influence the successful infection of cancer cells by these viruses. Here, we demonstrate that the cellular protein METTL3, which was previously shown to promote pancreatic cancer cell proliferation, invasion, and resistance to chemotherapy, plays a positive role in oncolytic virus replication in most of the tested human pancreatic cancer cell lines. We demonstrate that METTL3 depletion induces a chronic antiviral state that dramatically inhibits viral replication. Our study is important for understanding and improving oncolytic virus-based therapies.
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Affiliation(s)
- Cassandra Catacalos-Goad
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Jacob Hawkins
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Quinton Krueger
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
- Computational Intelligence to Predict Health and Environmental Risks (CIPHER) Center, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Nathaniel Foret
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
| | - Valery Z. Grdzelishvili
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
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23
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Shu QA, Huang XD, Wu J, Liang XR, Wang YL, Yu JM, Wang ZW, Liu N, Wang JH, Xie N. ARHGAP11A is a potential prognostic biomarker and therapeutic target for pancreatic adenocarcinoma. Int J Biochem Cell Biol 2025; 185:106804. [PMID: 40398712 DOI: 10.1016/j.biocel.2025.106804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/23/2024] [Accepted: 05/16/2025] [Indexed: 05/23/2025]
Abstract
The prognosis of pancreatic adenocarcinoma remains dismal up to now, partly owing to a lack of clinically feasible therapeutic targets. ARHGAP11A, a member of Rho GTPase-activating proteins family, has been reported as a prognostic biomarker and oncogene for multiple cancers. However, the specific effects of ARHGAP11A in pancreatic adenocarcinoma remain obscure. In this study, we explored and validated the oncogenic role of ARHGAP11A in pancreatic adenocarcinoma via thorough bioinformatics analyses of public databases and our own RNA-seq data, and in vitro experiments. We found that ARHGAP11A was significantly upregulated in pancreatic adenocarcinoma and correlated with poor clinical outcomes of pancreatic adenocarcinoma patients. Functional enrichment analyses revealed that ARHGAP11A-related genes were enriched in pathways of cell cycle and cell apoptosis. Further molecular functional experiments on ARHGAP11A knockdown pancreatic adenocarcinoma cell lines demonstrated that ARHGAP11A knockdown significantly inhibited cell proliferation, promoted cell cycle arrest in the G1/S stage, and induced cell apoptosis. In comparison, overexpression of ARHGAP11A could remarkably promote the proliferation, cell cycle progression, and apoptosis resistance of pancreatic adenocarcinoma cells. In conclusion, our study demonstrates that ARHGAP11A plays an oncogenic role in pancreatic adenocarcinoma, thus providing a novel therapeutic target and prognostic biomarker for patients with pancreatic adenocarcinoma.
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Affiliation(s)
- Qiu-Ai Shu
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xin-di Huang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Jian Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xi-Ru Liang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Ya-Lan Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Jin-Min Yu
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, China
| | - Zi-Wei Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Na Liu
- Department of Gastroenterology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan 570100, China.
| | - Jin-Hai Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
| | - Ning Xie
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
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24
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Tan HL, Zhao Y, Chua DW, Goh BKP, Koh YX. SEER-based evaluation of lymph node yield as a prognostic indicator of cancer-specific survival in nonmetastatic pancreatic ductal adenocarcinoma. Pancreatology 2025:S1424-3903(25)00093-6. [PMID: 40410047 DOI: 10.1016/j.pan.2025.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 05/10/2025] [Accepted: 05/15/2025] [Indexed: 05/25/2025]
Abstract
BACKGROUND/OBJECTIVES Although the American Joint Committee on Cancer (AJCC) 8th edition recommends harvesting at least 12 lymph nodes for optimal staging in pancreatic ductal adenocarcinoma (PDAC), the precise lymph node yield (LNY) needed for accurate prognostication in different treatment settings remains unclear. This study aimed to identify subgroup-specific LNY cutoffs and evaluate their prognostic significance in nonmetastatic PDAC. METHODS We analyzed 5609 patients with nonmetastatic PDAC from the Surveillance, Epidemiology, and End Results (SEER) database undergoing pancreatectomy. Patients were categorized by nodal status (N0 vs. N+) and receipt of neoadjuvant therapy (NAT) or upfront surgery (UPS). We used maximum selected rank statistics and a conditional inference tree approach to determine optimal LNY cutoffs for each subgroup. Kaplan-Meier curves and Cox proportional hazards models were employed to assess cancer-specific survival (CSS) and identify independent prognostic factors. RESULTS Distinct LNY thresholds were identified for N0 (>13) and N+ (>10) cohorts, with the highest cutoffs in N0-NAT subgroups (>27). Across all analyses, patients exceeding these LNY cutoffs demonstrated significantly prolonged CSS. The N0-NAT group with LNY >27 achieved the longest median survival (60 months), whereas N+ patients undergoing UPS with LNY ≤10 had the poorest outcomes (16 months). Multivariate Cox regressions consistently showed that higher LNY was an independent predictor of improved survival. CONCLUSIONS Higher LNY thresholds than the current AJCC standard of 12 appear beneficial for more accurate staging and improved survival in resected PDAC. Tailoring LNY goals based on nodal status and treatment modality may further refine prognostic stratification and guide more effective therapeutic strategies.
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Affiliation(s)
- Hwee Leong Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Academia, 20 College Road, 169856, Singapore; Duke-National University of Singapore Medical School, Singapore
| | - Yun Zhao
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Academia, 20 College Road, 169856, Singapore
| | - Darren Weiquan Chua
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Academia, 20 College Road, 169856, Singapore; Duke-National University of Singapore Medical School, Singapore; Liver Transplant Service, SingHealth Duke-National University of Singapore Transplant Centre, Singapore
| | - Brian Kim Poh Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Academia, 20 College Road, 169856, Singapore; Duke-National University of Singapore Medical School, Singapore; Liver Transplant Service, SingHealth Duke-National University of Singapore Transplant Centre, Singapore
| | - Ye Xin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Academia, 20 College Road, 169856, Singapore; Duke-National University of Singapore Medical School, Singapore; Liver Transplant Service, SingHealth Duke-National University of Singapore Transplant Centre, Singapore.
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25
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Ma T, Guo WW, Zhang M, He W, Dongzhi C, Gongye X, Xia P, Chai Y, Chen Z, Zhu Y, Qu C, Liu J, Yang Z, Ma W, Tian M, Yuan Y. Tumor-derived exosomal CCT6A serves as a matchmaker introducing chemokines to tumor-associated macrophages in pancreatic ductal adenocarcinoma. Cell Death Dis 2025; 16:382. [PMID: 40374617 DOI: 10.1038/s41419-025-07720-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 04/16/2025] [Accepted: 05/06/2025] [Indexed: 05/17/2025]
Abstract
M2-polarized tumor-associated macrophages (TAMs) are a key factor contributing to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). While various factors within the tumor microenvironment (TME) drive their formation, the role of PDAC-derived exosomes in this process remains unclear. We aim to clarify the regulatory impacts of tumor-derived exosomes to TAMs. After the intratumoral injection to subcutaneous tumor of C57BL/6 mice, we demonstrated PDAC-derived exosomes exacerbate PDAC progression, accompanied with upregulated M2 phenotype of TAMs and unaffected proliferation signatures. Through intratumoral injection model and multi-Omics analyses, we identified CCT6A as a novel tumor-derived exosomal protein, bridging TAMs M2 polarization and PDAC prognosis. Co-culture with exosomes derived from CCT6Ahigh PDAC leads to greater M2 phenotype of TAMs via PI3K-AKT signaling. According to proteomics data, chemokines' abundance reduces over tenfold once exosomal CCT6A absence, including CXCL1, CXCL3, CCL20 and CCL5, whose interaction with CCT6A in PDAC cells was confirmed by interactomics data. Moreover, we found silencing CCT6A abrogated the antagonism effects of CD47 antibody immunotherapy. Our findings implied that the subunit of the T-complex protein Ring Complex (TRiC) CCT6A serves as a matchmaker during exosome-mediated chemokines transfer from PDAC to TAMs. Silencing CCT6A effectively sensitized PDAC to CD47 antibody immunotherapy in vivo.
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Affiliation(s)
- Tianyin Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Wing-Wa Guo
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Minghe Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Wenzhi He
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Cairang Dongzhi
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Xiangdong Gongye
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
- Department of Chemistry and Molecular Biology, Sahlgrenska Akademin, Göteborg Universitet, Gothenburg, Vastra Gotalands, Sweden
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
- Department of Chemistry, The University of Chicago, Chicago, IL, USA
| | - Yibo Chai
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Zhang Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Yimin Zhu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Chengming Qu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Jie Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Zhiyong Yang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Ming Tian
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
- Taikang Center for Life and Medical Sciences of Wuhan University, Hubei, PR China.
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Yao XQ, Sabatinos SA, Da Silva E, Taggar A, Ha D, Khan R, Karshafian R, Gräfe J. Therapeutic enhancement effects using a lower energy 2.5 MV photon beam combined with gold nanoparticles on the BxPC-3 pancreatic cancer cell line, in vitro. Phys Med Biol 2025; 70:105017. [PMID: 40328291 DOI: 10.1088/1361-6560/add4b8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 05/06/2025] [Indexed: 05/08/2025]
Abstract
Objective. This study investigates the feasibility of using a clinically relevant lower energy 2.5 megavoltage (MV) photon beam in combination with gold nanoparticles (GNPs).Approach.Pancreatic cancer cell line, BxPC-3 impregnated with GNPs were exposedin vitroto 2.5 MV photon beam and compared with orthovoltage 225 kV and clinical 6 MV photon beam. Bare, 50 nm diameter, spherical GNPs were introduced in the cell culture 24 h prior to irradiation at a concentration of either 10μg ml-1or 50μg ml-1. GNP uptake was determined using inductively coupled plasma optical emission spectroscopy. The cells were irradiated with doses between 0 Gy to 8 Gy. Cell survival curves were obtained via clonogenic assay using immediate or delayed plating (24 h) methods 12 d after irradiation. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to evaluate DNA damage at two time points post irradiation, immediate and 24 h for 1 Gy and 6 Gy.Main results. The enhancement factor (EF) in BxPC-3 cells was greatest for cells incubated with 50μg ml-1of GNPs analyzed immediately post irradiation. Cells irradiated with 225 kV showed greatest EF (1.57 ± 0.15), followed by 2.5 MV (1.51 ± 0.04). The lowest EF was seen for 6 MV, immediate plating (1.10 ± 0.04). A significant increase in the number of DNA double strand breaks (DSB) was observed in cells incubated with 50μg ml-1of GNPs irradiated at 6 Gy with 225 kV and 2.5 MV. There was no significant increase in DSBs for the cells irradiated with 6 MV.Significance.These results suggest that the 2.5 MV could be a compromise between an orthovoltage energy beam and a clinical 6 MV beam, showing comparable reduction in cell survival to the 225 kV beam. Future GNP radiation enhancement research may focus on intermediate energy beams.
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Affiliation(s)
- Xiao Qing Yao
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), A Partnership Between Toronto Metropolitan University and St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario M5B 1T8, Canada
| | - Sarah A Sabatinos
- Department of Chemistry & Biology, Toronto Metropolitan University, Toronto M5B 2K3, Canada
| | - Eric Da Silva
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
| | - Amandeep Taggar
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto M4N 3M5, Canada
| | - Diana Ha
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
| | - Rao Khan
- Department of Physics and Astronomy, Howard University, Washington, DC, United States of America
| | - Raffi Karshafian
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), A Partnership Between Toronto Metropolitan University and St. Michael's Hospital, 209 Victoria Street, Toronto, Ontario M5B 1T8, Canada
| | - James Gräfe
- Department of Physics, Toronto Metropolitan University, Toronto, Ontario M5B 2K3, Canada
- Department of Medical Physics, Dr H. Bliss Murphy Cancer Centre, NL Health Services, St. John's, Newfoundland, Canada
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Hu X, Wang Z, Zhu Y, Li Z, Yan H, Zhao X, Wang Q. Advancements in molecular imaging for the diagnosis and treatment of pancreatic ductal adenocarcinoma. NANOSCALE ADVANCES 2025; 7:2887-2903. [PMID: 40270837 PMCID: PMC12012634 DOI: 10.1039/d4na01080a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 04/03/2025] [Indexed: 04/25/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor characterized by poor overall patient survival and prognosis, largely due to challenges in early diagnosis, limited surgical options, and a high propensity for therapy resistance. The integration of various imaging modalities through molecular imaging techniques, particularly multimodal molecular imaging, offers the potential to provide more precise and comprehensive information about the lesion. With advances in nanomedicine, new imaging and drug delivery approaches that allow the development of multifunctional theranostic agents offer opportunities for improving pancreatic cancer treatment using precision oncology. Herein, we review the diagnostic and therapeutic applications of molecular imaging for PDAC and discuss the adoption of multimodal imaging approaches that combine the strengths of different imaging techniques to enhance diagnostic accuracy and therapeutic efficacy. We emphasize the significant role of nanomedicine technology in advancing multimodal molecular imaging and theranostics, and their potential impact on PDAC management. This comprehensive review aims to serve as a valuable reference for researchers and clinicians, offering insights into the current state of molecular imaging in PDAC and outlining future directions for improving early diagnosis, combination therapies, and prognostic evaluations.
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Affiliation(s)
- Xun Hu
- Department of Diagnostic Imaging, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China
| | - Zihua Wang
- School of Basic Medical Sciences, Fujian Medical University Fuzhou 350122 Fujian Province China
| | - Yuting Zhu
- Department of Diagnostic Imaging, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China
| | - Zhangfu Li
- Department of Oral and Maxillofacial Surgery, Peking University Shenzhen Hospital Shenzhen Guangdong 518036 China
| | - Hao Yan
- Tsinghua Shenzhen International Graduate School/Tsinghua University Shenzhen 518055 China
| | - Xinming Zhao
- Department of Diagnostic Imaging, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China
| | - Qian Wang
- Department of Diagnostic Imaging, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China
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Kobayashi K, Sawada Y, Sahara K, Kikuchi Y, Miyake K, Yabushita Y, Homma Y, Kumamoto T, Matsuyama R, Endo I. Clinical Relevance of High-Grade Pancreatic Intraepithelial Neoplasia at the Pancreatic Transection Margin in Patients with Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 2025:10.1245/s10434-025-17400-y. [PMID: 40360836 DOI: 10.1245/s10434-025-17400-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/13/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND The clinical relevance of high-grade pancreatic intraepithelial neoplasia (PanIN) at the pancreatic transection margin (PTM) during resection of pancreatic ductal adenocarcinoma (PDAC) remains unclear. PATIENTS AND METHODS A total of 358 patients who underwent R0 resection for PDAC between January 2010 and December 2022 were included. The permanent sections used for the intraoperative frozen section diagnosis of PTM were evaluated for the PanIN grade. RESULTS Among 358 patients, 35 patients had low-grade PanIN (9.8%), and 17 had high-grade PanIN (4.7%) at the PTM. The 2-year overall survival (OS), disease-free survival (DSS), and relapse-free survival (RFS) did not differ markedly among patients with normal epithelium, low-grade PanIN, or high-grade PanIN at the margin. As the clinical features differed between patients with high-grade PanIN at the PTM and those without, we adjusted the patients' background factors using propensity score matching. The 2-year OS, DSS, and RFS rates were not significantly different between the groups. In addition, we investigated the details of 17 cases of high-grade PanIN in the PTM. The analysis revealed that 11 patients experienced recurrence after surgery. Among them, two cases of T1N0 showed recurrence in the remnant pancreas more than 2 years after surgery, while nine cases exhibited recurrence outside the remnant pancreas, such as the liver and lungs, within 2 years. CONCLUSIONS Patients with high-grade PanIN at the PTM did not show a significantly different prognosis than those without; however, recurrence in the remnant pancreas was observed in long-term survivors. Therefore, rigorous long-term follow-up is essential for such patients.
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Affiliation(s)
- Kei Kobayashi
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yu Sawada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Kota Sahara
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yutaro Kikuchi
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kentaro Miyake
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasuhiro Yabushita
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuki Homma
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takafumi Kumamoto
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Jia Y, Li J, Mei W, Zhang H, Wang Z, Xie X, Gao C, Xu X, Li F. Pan-HDAC inhibitor LAQ824 inhibits the progression of pancreatic ductal adenocarcinoma and suppresses immune escape by promoting antigen presentation. Int Immunopharmacol 2025; 154:114528. [PMID: 40158429 DOI: 10.1016/j.intimp.2025.114528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate. New drugs targeting pancreatic ductal adenocarcinoma (PDAC), the primary pathological subtype, are urgently needed. LAQ824, a novel pan-histone deacetylase inhibitor (HDACi), has shown anti-tumor activity in various cancers, but its effects on PDAC remain unexplored. This study investigates the therapeutic potential of LAQ824 in PDAC and its role in modulating immune escape mechanisms. Using a subcutaneous tumor model in C57BL/6 J mice, LAQ824's anti-tumor effects were evaluated. In vitro and in vivo experiments-including IHC, flow cytometry, RNA sequencing, and single-cell RNA sequencing-demonstrated that LAQ824 inhibits tumor proliferation, suppresses the epithelial-mesenchymal transition (EMT), and induces apoptosis. LAQ824 also enhances immunogenicity by upregulating MHC-I-mediated antigen presentation, increasing immune cell infiltration, and promoting CD8+ T cell maturation and differentiation. Mechanistically, LAQ824 upregulated MHC-I expression by enhancing chromatin accessibility of related genes, with HDAC1 identified as a key repressor of MHC-I in PDAC cells. In conclusion, we found that LAQ824 has a significant anti-tumor effect in PDAC. LAQ824 not only directly affects general biological behaviors such as proliferation, apoptosis, and EMT, but also increases the immunogenicity of tumor cells by upregulating the expression of MHC-I in PDAC, which promotes the antigen presentation process and enhances anti-tumor immunity. By showcasing LAQ824's potential as a therapeutic target against PDAC, the present study provides novel insights into the link between epigenetic regulation and immunogenicity in PDAC.
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Affiliation(s)
- Yuchen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Jie Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Wentong Mei
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China; Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Haoyu Zhang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Zheng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Xiaozhou Xie
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China
| | - Chongchong Gao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
| | - Xiaoqing Xu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
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Walczak ŁJ, Kosikowska U, Herbet M. The role and significance of the oncobiota in selected cancers: a review. Clin Exp Med 2025; 25:141. [PMID: 40335827 PMCID: PMC12058861 DOI: 10.1007/s10238-025-01598-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/10/2025] [Indexed: 05/09/2025]
Abstract
This review provides an overview of research evidence focused on the microbial components essential to clinical cancer care, called the oncobiota (the interaction of human microbiota and cancer cells). It specifically examines the oncobiota in central nervous system cancer,breast cancer, pancreatic cancer, liver cancer, lung cancer, and cervical cancer. The literature review reveals insufficient knowledge about the oncobiota of organs once considered sterile. Many studies on oncobiota focus on small, geographically specific patient groups, and the absence of a reference (control) group complicates the development of microbial profiles for selected cancers. Consequently, this review aims to analyze the literature data and reports on the role of oncobiota in selected "sterile" organs and the resulting therapeutic or preventive implications. All relevant publications on oncobiota in patients with the selected cancers were considered to provide the most thorough analysis possible. Understanding the significance and role of oncobiota in the pathomechanisms of carcinogenesis may pave the way for targeted cancer prevention methods. Furthermore, therapeutic strategies based on oncobiota could represent a novel area of personalized cancer treatment. Additionally, oncobiota may serve as an additional diagnostic tool in oncology.
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Affiliation(s)
- Łucja Justyna Walczak
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8 Chodźki Street, 20-093, Lublin, Poland.
| | - Urszula Kosikowska
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Medical University of Lublin, 1 Chodźki Street, 20-093, Lublin, Poland.
| | - Mariola Herbet
- Chair and Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8 Chodźki Street, 20-093, Lublin, Poland
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Zhang Y, Esmail A, Hassanain H, Dhillon V, Abdelrahim W, Al-Najjar E, Khasawneh B, Abdelrahim M. Correlative Analysis of Tumor-Informed Circulating Tumor DNA (ctDNA) and the Survival Outcomes of Patients with Pancreatic Adenocarcinoma. Biomedicines 2025; 13:1124. [PMID: 40426952 PMCID: PMC12108567 DOI: 10.3390/biomedicines13051124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis due to late-stage diagnosis, limited surgical resectability, and frequent recurrence. Traditional biomarkers like CA19-9 and imaging techniques often fail to detect minimal residual disease (MRD) or early recurrence. Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker that may provide early detection of disease recurrence, offering a potential improvement in patient management. This study aimed to assess the utility of ctDNA as a prognostic tool for PDAC patients, specifically in predicting recurrence and overall survival (OS). Methods: This retrospective study analyzed data from 39 PDAC patients who underwent surgery and were monitored for ctDNA levels using Signatera™, a tumor-informed multiplex PCR next-generation sequencing assay. Blood samples were collected both preoperatively and postoperatively, and ctDNA levels were measured to detect MRD. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctDNA were compared with CA19-9 in detecting disease recurrence. Clinical outcomes, including progression-free survival (PFS) and OS, were evaluated in relation to ctDNA status. Results: Among 39 patients, 153 plasma samples were analyzed, with 17 patients testing positive for ctDNA. Sensitivity of ctDNA in detecting relapse was 91%, compared to 83% for CA19-9, with combined testing reaching 98% sensitivity. ctDNA positivity was associated with significantly shorter OS and PFS, with patients testing negative for ctDNA having a median OS of 37.6 months versus 13.4 months in ctDNA-positive patients (p = 0.003). The median time from ctDNA positivity to imaging-confirmed relapse was 81 days. Positive ctDNA was also linked to higher rates of lymphovascular invasion and positive surgical margins, highlighting the aggressive nature of the disease in these patients. Conclusions: CtDNA is a highly sensitive and specific biomarker for detecting MRD and predicting recurrence in PDAC patients, offering superior performance over CA19-9. Positive ctDNA results were associated with worse prognosis, including shorter OS and PFS, and may help guide treatment decisions. These findings suggest that ctDNA could be a valuable tool for personalized management in PDAC, though further prospective studies are needed to validate its clinical role in treatment stratification.
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Affiliation(s)
- Yuqi Zhang
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Hala Hassanain
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Vikramjit Dhillon
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Waseem Abdelrahim
- Michael E. DeBakey HS for Health Professions, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Bayan Khasawneh
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77094, USA
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Li Z, Zhang T, Yang X, Peng Y. Role of noncoding RNA and protein interaction in pancreatic cancer. Chin Med J (Engl) 2025; 138:1019-1036. [PMID: 40205638 PMCID: PMC12068769 DOI: 10.1097/cm9.0000000000003587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Indexed: 04/11/2025] Open
Abstract
ABSTRACT Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA-protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA-protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.
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Affiliation(s)
- Zhang Li
- Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tingting Zhang
- Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaojuan Yang
- Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yong Peng
- Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Wong P, Tran TB, Pollini T, Hernandez S, Zampese M, Todeschini L, Aguilar LL, Maker VK, Maker AV. Impact of coronary artery stenting on perioperative mortality and complications in patients undergoing pancreaticoduodenectomy. J Gastrointest Surg 2025; 29:102020. [PMID: 40118202 DOI: 10.1016/j.gassur.2025.102020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 03/03/2025] [Accepted: 03/15/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND Postoperative morbidity and mortality rates from pancreaticoduodenectomy (PD) have significantly decreased, allowing for greater consideration of patients with severe comorbidities. This study aimed to evaluate the effect of previous coronary artery intervention on morbidity and mortality among patients who underwent PD. METHODS Patients who underwent PD were identified from the American College of Surgeon National Surgical Quality Improvement Program database. Patients with previous coronary artery intervention received either balloon dilatation or stent placement. The main outcome measures included in-hospital mortality and postoperative myocardial infarction (MI). RESULTS Of 10,848 patients who underwent PD, 698 (6.4%) received previous coronary artery intervention. Compared with patients without coronary artery intervention, those with previous coronary artery intervention were older (65 vs 70 years, respectively; P <.001), were less likely to be female (50.2% vs 26.4%, respectively; P <.001), and had higher median body mass index (26 vs 27 kg/m2, respectively; P =.003). Compared with patients not in the angioplasty/stent cohort, those in the angioplasty/stent cohort were more likely to have diabetes mellitus (22.0% vs 39.3%, respectively), functional impairment (2.4% vs 4.9%, respectively), chronic obstructive pulmonary disease (4.1% vs 8.2%, respectively), hypertension (51.2% vs 86.2%, respectively), and bleeding disorders (2.2% vs 8.0%, respectively) (all P <.001). Compared with patients not in the angioplasty/stent cohort, those in the stent/angioplasty group were more likely to have postoperative complications (41.0% vs 51.4%, respectively; P <.001). Previous stent/angioplasty procedure (odds ratio [OR], 2.61 [95% CI, 1.42-4.57]; P =.001) was associated with developing postoperative MI but was not an independent predictor of in-hospital mortality (OR, 1.19 [95% CI, 0.81-1.70]; P =.369). CONCLUSION Previous stent placement/angioplasty was not associated with increased in-hospital mortality in patients who underwent PD, despite being correlated with an increased risk of MI and severe complications. Previous coronary artery angioplasty and/or stenting is not an absolute contraindication for PD, but patients should be medically optimized preoperatively to mitigate the risk of major adverse cardiac events.
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Affiliation(s)
- Paul Wong
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Thuy B Tran
- Division of Surgical Oncology, Department of Surgery, University of Illinois Chicago, Chicago, IL, United States
| | - Tommaso Pollini
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Sophia Hernandez
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Marco Zampese
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Letizia Todeschini
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Luis Laurean Aguilar
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Vijay K Maker
- Division of Surgical Oncology, Department of Surgery, University of Illinois Chicago, Chicago, IL, United States
| | - Ajay V Maker
- Division of Surgical Oncology, Department of Surgery, University of California San Francisco, San Francisco, CA, United States.
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Eikenboom EL, Nasar N, Seier K, Gönen M, Spaander MCW, O'Reilly EM, Jarnagin WR, Drebin J, D'Angelica MI, Kingham TP, Balachandran VP, Soares KC, Wagner A, Wei AC. Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas. Ann Surg Oncol 2025; 32:3568-3577. [PMID: 39656390 DOI: 10.1245/s10434-024-16621-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 11/19/2024] [Indexed: 04/24/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare. METHODS This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts. RESULTS Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%]). CONCLUSION Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.
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Affiliation(s)
- Ellis L Eikenboom
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Naaz Nasar
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Seier
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey Drebin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin C Soares
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alice C Wei
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Patel S, Jenkins E, Kusurkar RP, Lee S, Jiang W, Nevler A, McCoy M, Pishvaian MJ, Sears RC, Brody JR, Yeo CJ, Jain A. Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma. Neoplasia 2025; 63:101152. [PMID: 40096771 PMCID: PMC11957605 DOI: 10.1016/j.neo.2025.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/19/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC.
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Affiliation(s)
- Sohum Patel
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Eleanor Jenkins
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Rutuj P Kusurkar
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sherry Lee
- Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Wei Jiang
- Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Avinoam Nevler
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Matthew McCoy
- Innovation Center for Biomedical Informatics & Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Michael J Pishvaian
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Rosalie C Sears
- Department of Molecular and Medical Genetics, and Brenden-Colson Center for Pancreatic Care Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jonathan R Brody
- Department of Surgery, and Brenden-Colson Center for Pancreatic Care Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Charles J Yeo
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Aditi Jain
- Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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Kuijper SC, Gehrels AM, van der Geest LG, Verhoeven RHA, Koerkamp BG, Molenaar IQ, Stommel MWJ, de Meijer VE, de Vos‐Geelen J, Wumkes ML, Besselink MG, Wilmink JW, van Laarhoven HWM, for the Dutch Pancreatic Cancer Group. Survival scenarios of patients with localized and metastatic pancreatic adenocarcinoma: A population-based study. Int J Cancer 2025; 156:1726-1735. [PMID: 39614657 PMCID: PMC11887001 DOI: 10.1002/ijc.35267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/25/2024] [Accepted: 10/01/2024] [Indexed: 12/01/2024]
Abstract
Pancreatic adenocarcinoma (PAC) is notorious for its poor survival. The provision of survival scenarios-that is, best-case, typical and worst-case scenarios-could prove valuable to patients and clinicians. This study investigated survival scenarios and how these have changed over a period of 16 years for patients with PAC. Data from the Netherlands Cancer Registry were used to identify patients with localized and metastatic PAC (2005-2021). Survival scenarios, including best-case, upper-typical, typical (median), lower-typical, and worst-case, were estimated based on survival curve percentiles (p10, p25, p50, p75, and p90). Annual differences were assessed for significance using weighted linear regression analyses. Factors associated with these scenarios were identified through univariable tests. Overall, 14,622 patients with localized and 20,199 with metastatic PAC were included. For patients with localized PAC, the best, upper-typical and typical survival scenarios improved statistically significant with average annual improvement of 1.54 (95%CI: 1.2-1.88), 0.67 (0.56-0.78), and 0.24 (0.19-0.29) months, respectively. For patients with metastatic PAC the best and upper-typical survival scenarios increased statically significantly with annual improvement of 0.28 (0.21-0.34) and 0.06 (0.02-0.09) months, respectively. The best-case and upper-typical scenarios were associated with younger patients, more aggressive disease-focused treatments, fewer comorbidities, and better overall performance status. Over the past 16 years, survival improvements in patients with PAC have been most notable in these scenarios. Although the absolute gains were modest, these results offer encouraging potential for advancements in life-prolonging care for this type of cancer.
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Affiliation(s)
- Steven C. Kuijper
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
| | - Anne M. Gehrels
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
| | - Lydia G. van der Geest
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
- Department of Research & DevelopmentNetherlands Comprehensive Cancer Organisation (IKNL)UtrechtThe Netherlands
| | - Rob H. A. Verhoeven
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
- Department of Research & DevelopmentNetherlands Comprehensive Cancer Organisation (IKNL)UtrechtThe Netherlands
| | - Bas Groot Koerkamp
- Department of SurgeryErasmus MC Cancer InstituteRotterdamThe Netherlands
| | - I. Quintus Molenaar
- Department of Surgery, Regional Academic Cancer Center UtrechtUniversity Medical Center Utrecht and St. Antonius Hospital NieuwegeinUtrechtThe Netherlands
| | | | - Vincent E. de Meijer
- Department of SurgeryUniversity of Groningen and University Medical Center GroningenGroningenThe Netherlands
| | - J. de Vos‐Geelen
- Department of Internal Medicine, Division of Medical OncologyMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Miriam L. Wumkes
- Department of Medical OncologyJeroen Bosch HospitalDen BoschThe Netherlands
| | - Marc G. Besselink
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
- Amsterdam UMC, location University of AmsterdamDepartment of SurgeryAmsterdamThe Netherlands
| | - Johanna W. Wilmink
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
| | - Hanneke W. M. van Laarhoven
- Department of Medical OncologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer Treatment and Quality of LifeAmsterdamThe Netherlands
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Hao YH, Yang CR, Shi WJ, Zhong XY. PSMD14 Transcriptionally Activated by MEF2A Promotes Pancreatic Cancer Development by Upregulating SPON2 Expression. Kaohsiung J Med Sci 2025; 41:e70007. [PMID: 40066751 DOI: 10.1002/kjm2.70007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/02/2025] [Accepted: 02/19/2025] [Indexed: 05/16/2025] Open
Abstract
Proteasome 26S subunit non-ATPase 14 (PSMD14) plays a pro-carcinogenic role in various cancers. However, its specific effects and mechanisms in pancreatic cancer (PC) remain unclear. We aimed to assess the function and mechanism of PSMD14 in PC. Fifteen paired pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent non-tumorous tissues were clinically obtained. Cell proliferation, migration, and invasion were assessed using colony formation, scratch, and Transwell assays. The interaction between the MEF2A transcription factor and the PSMD14 promoter verified by chromatin immunoprecipitation (ChIP) or dual luciferase assay. The interaction between RBM15B and SPON2 mRNA was validated by RNA immunoprecipitation (RIP) assay. The interaction between the proteins PSMD14 and RBM15B was detected by co-immunoprecipitation (Co-IP) assay. The m6A level of SPON2 was detected by methylated RNA immunoprecipitation (MeRIP, a common method for detecting m6A levels of mRNAs). The ubiquitination level of RNA-binding motif protein 15B (RBM15B) was detected using Co-IP. The role of PSMD14 in PC was further explored subcutaneous and lung metastasis models. PSMD14 was upregulated in PDAC tissues. PSMD14 knockdown inhibited PC cell viability, proliferation, migration, and invasion. MEF2A transcriptionally activated PSMD14 expression. PSMD14 knockdown promoted the ubiquitination degradation of RBM15B. Additionally, PSMD14 enhanced SPON2 mRNA stability through RBM15B-mediated m6A modification. SPON2 overexpression impaired the effect of knockdown PSMD14. Finally, PSMD14 knockdown in PC arrested tumor growth and lung metastasis. PSMD14, transcriptionally activated by MEF2A, promotes the de-ubiquitination of RBM15B, which upregulates SPON2 expression in an m6A-RBM15B-dependent manner, thereby facilitating PC proliferation, migration, and invasion.
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Affiliation(s)
- Yun-He Hao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Cheng-Ru Yang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wu-Jiang Shi
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiang-Yu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Lin Q, Guan S, Peng M, Zhang K, Zhang H, Mo T, Yu H. Comprehensive analysis of SQOR involvement in ferroptosis resistance of pancreatic ductal adenocarcinoma in hypoxic environments. Front Immunol 2025; 16:1513589. [PMID: 40375994 PMCID: PMC12078260 DOI: 10.3389/fimmu.2025.1513589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 04/07/2025] [Indexed: 05/18/2025] Open
Abstract
Introduction Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance. Methods Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis. Results PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner. Discussion This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.
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Affiliation(s)
- Quan Lin
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shiwei Guan
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Minghui Peng
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kailun Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hewei Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Taoming Mo
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Haibo Yu
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Thereaux J, Badic B, Fuchs B, Leven C, Caillard A, Lacut K, Metges JP, Couturaud F. Comprehensive assessment of 1-year postoperative venous thromboembolism and associated mortality risks in hepatopancreatobiliary cancer surgeries: A national survey. Surgery 2025; 181:109171. [PMID: 39952022 DOI: 10.1016/j.surg.2025.109171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/13/2024] [Accepted: 01/08/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Venous thromboembolism is a well-recognized complication after hepatopancreatobiliary surgery. However, there is a paucity of nationwide data on risk factors and incidence within 1 year of surgery in patients undergoing hepatopancreatobiliary surgery. METHODS This nationwide observational population-based cohort study used data extracted from all patients undergoing surgery for cancer surgery of the liver and the pancreas in France between 1 January 2015 and 31 December 2017. Estimation of 1 postoperative year cumulative incidence of venous thromboembolism and Cox proportional hazards model on 1-year global mortality were performed. RESULTS During the study period, 16,960 patients underwent cancer surgery of the liver (n = 9,381) or pancreas (n = 7,579). The 90-day postoperative rate of venous thromboembolism was 6.1% (cancer surgery of the liver) and 6.7% (cancer surgery of the pancreas). Main risk factors of 90-day postoperative rate of venous thromboembolism were major hepatectomy (1.85; 1.55-2.21), left pancreatectomy (1.45; 1.18-1.79), presence of obesity (1.41; 1.16-1.71), history of venous thromboembolism (4.58; 3.41-6.14), open approach (1.31; 1.06-1.62), and the occurrence of serious surgical complication (1.55; 1.35-1.79). At 1 year, patients undergoing cancer surgery of the liver were at a lower risk of cumulative incidence (%) of venous thromboembolism compared with the cancer surgery of the pancreas group (P < .001) (7.0; 6.5-7.6 vs 9.8; 9.1-10.4). Patients with venous thromboembolism within 1 year had greater risks of 1-year global mortality for each hepatopancreatobiliary surgery group: 3.58 (95% confidence interval, 3.02-4.23) and 3.97 (95% confidence interval, 3.40-4.63), respectively. CONCLUSION Postoperative venous thromboembolism is a significant issue after hepatopancreatobiliary surgery, within 90 days postoperatively and up to 1 year, with the cancer surgery of the pancreas group being particularly at risk. A greater risk of global mortality within 1 year for patients experiencing early or late venous thromboembolism was found.
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Affiliation(s)
- Jérémie Thereaux
- University Brest, CHU Brest, Brest, France; Department of General, Digestive and Metabolic Surgery, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France.
| | - Bogdan Badic
- Department of General, Digestive and Metabolic Surgery, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France; Univ Brest, CHU Brest, UMR 1304, Western Brittany Thrombosis Group, Brest, France
| | - Basil Fuchs
- Department of Medical Information, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France
| | - Cyril Leven
- University Brest, CHU Brest, Brest, France; Department of Biochemistry and Pharmaco-Toxicology, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France
| | - Anais Caillard
- Department of Anesthesia and Intensive Care, La Cavale Blanche and Morvan University Hospitals, Boulevard Tanguy Prigent, Brest, France
| | - Karin Lacut
- University Brest, CHU Brest, Brest, France; Department of Internal Medicine, Vascular Medicine and Pneumology, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France
| | | | - Francis Couturaud
- University Brest, CHU Brest, Brest, France; Department of Internal Medicine, Vascular Medicine and Pneumology, La Cavale Blanche University Hospital, Boulevard Tanguy Prigent, Brest, France
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CHENG X, YU W, WANG D, JIANG L, HU L. [Enriching plasma exosomes for proteomic analysis using a phosphatidylserine-imprinted polymer]. Se Pu 2025; 43:539-546. [PMID: 40331617 PMCID: PMC12059983 DOI: 10.3724/sp.j.1123.2024.05003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Indexed: 05/08/2025] Open
Abstract
Exosomes are 40-160 nm vesicular nano-bodies secreted by most cells that carry large amounts of biologically active substances originating from the parent cell. Proteins in exosomes are protected by phospholipid bilayer membranes that protect them from degradation by enzymes within body fluids. Along with nucleic acid, proteins and metabolites, exosomes are biomolecules that are considered to be among the most important for discovering tumor markers. Plasma is among the most commonly used body fluids in clinical settings; it is highly complex and contains many proteins and metabolites that interfere with exosome isolation. Consequently, the development of methods for effectively isolating exosomes is a key challenge prior to their use in clinical research. In this study, we used a phosphatidylserine molecularly imprinted polymer (PS-MIP) to enrich plasma exosomes. Subsequent immunoblotting analyses for the CD9, TSG101, and CD81 exosome marker proteins showed that signals can be detected using only 5 μL of plasma, thereby demonstrating the efficiency and specificity of the enrichment protocol. Transmission electron microscope (TEM) and nanoparticle tracking analysis (NTA) data revealed that the enriched vesicles are 30-100 nm in size with elliptical or cup-shaped structures, consistent with the morphology and particle-size-distribution characteristics of the exosomes, suggesting that PS-MIP is capable of successfully isolating exosomes. Nanoflow cytometry revealed that 75.4% of the multi-angle laser scattering (MALS) signal is derived from the PS-MIP-enriched exosomes, which indicates that these enriched exosomes are highly pure and free of interference from impurities, such as aggregated protein particles that are similar in size to the exosomes themselves. This method was used to analyze the proteomes and potential exosomal protein markers of clinical plasma samples from three pancreatic-cancer patients and three healthy volunteers. A total of 1052 proteins and 4545 peptides were identified in the plasma exosomes of healthy volunteers, with a total of 972 proteins and 4096 peptides identified in the plasma exosomes of the pancreatic-cancer patients. Further bioinformatics analyses revealed that the Vesiclepedia database covered 84% of the proteins identified in the plasma exosomes isolated using the PS-MIP method; these proteins comprise 77 of the 100 most frequently identified exosomal proteins in the ExoCarta database. The identified proteins from the cellular components were subjected to gene ontology (GO) analysis, which revealed that they are mainly derived from the exosomes, thereby demonstrating the high selectivity of the PS-MIP method for enriching plasma exosomes and providing specificity for subsequent tumor-marker screening. Label-free quantitative analysis showed that 11 proteins were upregulated and 24 proteins were downregulated in the plasma exosomes of patients with pancreatic cancer compared to those of healthy volunteers. The highly expressed and lowly expressed proteins in the plasma exosomes of patients with pancreatic cancer were subjected to GO, which showed that highly expressed proteins related to the positive regulation of metabolic and biological processes were found in the plasma exosomes of patients with pancreatic cancer compared to those of healthy volunteers, whereas the most significantly under-expressed proteins are related immune-system processes, followed by stimulus-responsive, multicellular bioprocesses, bioregulatory, and interspecies-interacting biological-process-related proteins. The top three proteins, which are relatively highly correlated through protein-protein interaction networks (PPI) analysis, were determined to be complement factor D (CFD), complement component 3 (C3), and von Willebrand factor (VWF). Among the upregulated proteins in the exosomes of patients with pancreatic cancer, exostosin-like glycosyltransferase 2 (EXTL2), α-2-macroglobulin like 1 (A2ML1), and Parkinson's disease protein 7 (PARK7) were the most significantly overexpressed. Hence, these proteins are potential biomarkers for the diagnostic and prognostic assessment of pancreatic cancer and may provide support for further clinical studies into pancreatic cancer.
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Zhang Y, Xu M, Wang Y, Yu F, Chen X, Wang G, Zhao K, Yang H, Su X. Value of [ 18F]AlF-NOTA-FAPI-04 PET/CT for predicting pathological response and survival in patients with locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant chemotherapy. Eur J Nucl Med Mol Imaging 2025; 52:2118-2131. [PMID: 39820598 DOI: 10.1007/s00259-025-07084-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/10/2025] [Indexed: 01/19/2025]
Abstract
OBJECTIVES This study aimed to evaluate the predictive value of [18F]AlF-NOTA-FAPI-04 PET/CT for pathological response to neoadjuvant chemotherapy (NCT) and prognosis in patients with locally advanced pancreatic ductal adenocarcinoma (LAPDAC). METHODS This study included 34 patients with histopathologically and radiologically confirmed LAPDAC who received [18F]AlF-NOTA-FAPI-04 PET/CT scans before NCT. After 4-6 cycles of NCT, these patients underwent radical resection. Pathological response to NCT was assessed by pathological tumor regression grades (TRG) based on the Evans system. PET/CT parameters were evaluated for their association with TRG, recurrence-free survival (RFS) and overall survival (OS) after NCT, including the maximum standardized uptake value (SUVmax), FAPI-avid tumor volume (FTV), total lesion FAP expression (TLF) of primary tumor, total FAPI-avid pancreatic volume (FPV) and total pancreatic FAP expression (TPF) of total pancreas. RESULTS Of 34 patients with LAPDAC, 14 patients had a pathologic good response (PGR, Evans III-IV), and 20 patients had a pathologic poor response (PPR, Evans I-II). Both the primary tumor SUVmax, FTV and TLF, and total pancreas FPV and TPF in the PGR groups were significantly lower than those in the PPR groups. Furthermore, SUVmax and TLF were higher in poorly differentiated LAPDAC than in well-moderately differentiated neoplasms. The FTV, TLF, FPV and TPF were closely associated with RFS and OS. On multivariate analysis, patients with FTV > 54.21 and TLF > 290.21 had a worse RFS and OS, respectively (HR = 3.24, P = 0.014 and HR = 3.35, P = 0.019) and OS (HR = 7.35, P = 0.002 and HR = 7.09, P = 0.004) in LAPDAC after NCT. CONCLUSIONS The parameters of [18F]AlF-NOTA-FAPI-04 PET/CT had the excellent performance for predicting pathologic TRG after NCT in LAPDAC. FTV and TLF were independent postoperative prognostic factors for RFS and OS for LAPDAC.
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Affiliation(s)
- Yafei Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Mimi Xu
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Yu Wang
- Department of Pharmacy, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China
| | - Fang Yu
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xinxin Chen
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Guangfa Wang
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Kui Zhao
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Hong Yang
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
| | - Xinhui Su
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
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Rangelova E, Stoop TF, van Ramshorst TME, Ali M, van Bodegraven EA, Javed AA, Hashimoto D, Steyerberg E, Banerjee A, Jain A, Sauvanet A, Serrablo A, Giani A, Giardino A, Zerbi A, Arshad A, Wijma AG, Coratti A, Zironda A, Socratous A, Rojas A, Halimi A, Ejaz A, Oba A, Patel BY, Björnsson B, Reames BN, Tingstedt B, Goh BKP, Payá-Llorente C, Del Pozo CD, González-Abós C, Medin C, van Eijck CHJ, de Ponthaud C, Takishita C, Schwabl C, Månsson C, Ricci C, Thiels CA, Douchi D, Hughes DL, Kilburn D, Flanking D, Kleive D, Silva DS, Edil BH, Pando E, Moltzer E, Kauffman EF, Warren E, Bozkurt E, Sparrelid E, Thoma E, Verkolf E, Ausania F, Giannone F, Hüttner FJ, Burdio F, Souche FR, Berrevoet F, Daams F, Motoi F, Saliba G, Kazemier G, Roeyen G, Nappo G, Butturini G, Ferrari G, Kito Fusai G, Honda G, Sergeant G, Karteszi H, Takami H, Suto H, Matsumoto I, Mora-Oliver I, Frigerio I, Fabre JM, Chen J, Sham JG, Davide J, Urdzik J, de Martino J, Nielsen K, Okano K, Kamei K, Okada K, Tanaka K, Labori KJ, Goodsell KE, Alberici L, Webber L, Kirkov L, de Franco L, Miyashita M, Maglione M, Gramellini M, Ramera M, Amaral MJ, et alRangelova E, Stoop TF, van Ramshorst TME, Ali M, van Bodegraven EA, Javed AA, Hashimoto D, Steyerberg E, Banerjee A, Jain A, Sauvanet A, Serrablo A, Giani A, Giardino A, Zerbi A, Arshad A, Wijma AG, Coratti A, Zironda A, Socratous A, Rojas A, Halimi A, Ejaz A, Oba A, Patel BY, Björnsson B, Reames BN, Tingstedt B, Goh BKP, Payá-Llorente C, Del Pozo CD, González-Abós C, Medin C, van Eijck CHJ, de Ponthaud C, Takishita C, Schwabl C, Månsson C, Ricci C, Thiels CA, Douchi D, Hughes DL, Kilburn D, Flanking D, Kleive D, Silva DS, Edil BH, Pando E, Moltzer E, Kauffman EF, Warren E, Bozkurt E, Sparrelid E, Thoma E, Verkolf E, Ausania F, Giannone F, Hüttner FJ, Burdio F, Souche FR, Berrevoet F, Daams F, Motoi F, Saliba G, Kazemier G, Roeyen G, Nappo G, Butturini G, Ferrari G, Kito Fusai G, Honda G, Sergeant G, Karteszi H, Takami H, Suto H, Matsumoto I, Mora-Oliver I, Frigerio I, Fabre JM, Chen J, Sham JG, Davide J, Urdzik J, de Martino J, Nielsen K, Okano K, Kamei K, Okada K, Tanaka K, Labori KJ, Goodsell KE, Alberici L, Webber L, Kirkov L, de Franco L, Miyashita M, Maglione M, Gramellini M, Ramera M, Amaral MJ, Ramaekers M, Truty MJ, van Dam MA, Stommel MWJ, Petrikowski M, Imamura M, Hayashi M, D'Hondt M, Brunner M, Hogg ME, Zhang C, Suárez-Muñoz MÁ, Luyer MD, Unno M, Mizuma M, Janot M, Sahakyan MA, Jamieson NB, Busch OR, Bilge O, Belyaev O, Franklin O, Sánchez-Velázquez P, Pessaux P, Holka PS, Ghorbani P, Casadei R, Sartoris R, Schulick RD, Grützmann R, Sutcliffe R, Mata R, Patel RB, Takahashi R, Rodriguez Franco S, Cabús SS, Hirano S, Gaujoux S, Festen S, Kozono S, Maithel SK, Chai SM, Yamaki S, van Laarhoven S, Mieog JSD, Murakami T, Codjia T, Sumiyoshi T, Karsten TM, Nakamura T, Sugawara T, Boggi U, Hartman V, de Meijer VE, Bartholomä W, Kwon W, Koh YX, Cho Y, Takeyama Y, Inoue Y, Nagakawa Y, Kawamoto Y, Ome Y, Soonawalla Z, Uemura K, Wolfgang CL, Jang JY, Padbury R, Satoi S, Messersmith W, Wilmink JW, Abu Hilal M, Besselink MG, Del Chiaro M. The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study. Ann Oncol 2025; 36:529-542. [PMID: 39814200 DOI: 10.1016/j.annonc.2024.12.015] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/26/2024] [Accepted: 12/23/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Left-sided pancreatic cancer is associated with worse overall survival (OS) compared with right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with resectable pancreatic cancer (RPC), current randomized trials included mostly patients with right-sided RPC. The purpose of this study was to assess the association between neoadjuvant therapy and OS in patients with left-sided RPC compared with upfront surgery. PATIENTS AND METHODS This was an international multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). The primary endpoint was OS from diagnosis. Time-dependent Cox regression analysis was carried out to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at the time of diagnosis. Adjusted OS probabilities were calculated. RESULTS Overall, 2282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared with upfront surgery (adjusted hazard ratio 0.69, 95% confidence interval 0.58-0.83) with an adjusted median OS of 53 versus 37 months (P = 0.0003) and adjusted 5-year OS rates of 47% versus 35% (P = 0.0001) compared with upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction = 0.003) and higher serum carbohydrate antigen 19-9 (CA19-9; Pinteraction = 0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction = 0.43), splenic vein (Pinteraction = 0.30), retroperitoneal (Pinteraction = 0.84), and multivisceral (Pinteraction = 0.96) involvement. CONCLUSIONS Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared with upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.
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Affiliation(s)
- E Rangelova
- Department of Upper Abdominal Surgery at Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
| | - T F Stoop
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands; Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA
| | - T M E van Ramshorst
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Surgery, Fondazione Poliambulanza, Instituto Ospedaliero, Brescia, Italy
| | - M Ali
- Cancer Center Amsterdam, Amsterdam, The Netherlands; Amsterdam UMC, Location Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands
| | - E A van Bodegraven
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - A A Javed
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Surgical Oncology, Department of Surgery, New York University Medical Center, New York, USA
| | - D Hashimoto
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - E Steyerberg
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - A Banerjee
- HPB & Liver Transplant Unit, Royal Free Hospital, London, UK
| | - A Jain
- Division of Surgical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - A Sauvanet
- Department of HPB Surgery and Liver Transplantation, APHP Beaujon Hospital, University of Paris Cité, Clichy, France
| | - A Serrablo
- HPB Surgical Division, Miguel Servet University Hospital, Zaragoza, Spain
| | - A Giani
- Division of Minimally-Invasive Surgical Oncology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Giardino
- Department of HPB Surgery, Pederzoli Hospital, Peschiera del Garda, Peschiera, Italy
| | - A Zerbi
- Humanitas University, Department of Biomedical Sciences, Milan, Italy; Pancreatic Surgery Unit, Humanitas Clinical and Research Center, IRCCS, Milan, Italy
| | - A Arshad
- Hepatopancreatobiliary Unit, University Hospitals Southampton NHS Trust, Southampton General Hospital, Southampton, UK
| | - A G Wijma
- Department of Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - A Coratti
- General and Emergency Surgery Unit, Misericordia Hospital, Azienda USL Toscana Sud-Est, Grosseto, Italy
| | - A Zironda
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, USA
| | - A Socratous
- Department of Upper Abdominal Surgery at Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - A Rojas
- Department of Surgery, NorthShore University Health System, Evanston, USA
| | - A Halimi
- Department of Surgery, Umeå University, Umeå, Sweden; Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - A Ejaz
- Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, USA
| | - A Oba
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA; Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo; Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - B Y Patel
- Hepatopancreatobiliary Unit, University Hospitals Southampton NHS Trust, Southampton General Hospital, Southampton, UK
| | - B Björnsson
- Department of Surgery, Linköping University Hospital, Linköping, Sweden
| | - B N Reames
- Department of Surgery, University of Nebraska Medical Center, Omaha, USA
| | - B Tingstedt
- Department of Clinical Sciences Lund, Surgery, Lund University, Skåne University Hospital, Lund, Sweden
| | - B K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore
| | - C Payá-Llorente
- General and Digestive Surgery, Hospital Doctor Peset, Valencia, Spain
| | - C D Del Pozo
- General and Digestive Surgery, Hospital Doctor Peset, Valencia, Spain
| | - C González-Abós
- Hepatobiliopancreatic Department, Hospital Clinic de Barcelona, Barcelona, Spain
| | - C Medin
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA
| | - C H J van Eijck
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - C de Ponthaud
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
| | - C Takishita
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - C Schwabl
- Department of Radiology, Medical University Innsbruck, Innsbruck, Austria
| | - C Månsson
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - C Ricci
- Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy; Division of Pancreatic Surgery, IRCCS, Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
| | - C A Thiels
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, USA
| | - D Douchi
- Department of Surgery, Tohoku University, Sendai, Japan
| | - D L Hughes
- Department of Hepatobiliary and Pancreatic Surgery, Oxford Radcliffe Hospitals NHS Foundation Trust, Oxford, UK
| | - D Kilburn
- Department of Surgery, Flinders Medical Centre, Adelaide, Australia
| | - D Flanking
- Department of Upper Abdominal Surgery at Sahlgrenska University Hospital, Gothenburg, Sweden
| | - D Kleive
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - D S Silva
- HEBIPA Surgery, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - B H Edil
- Division of Surgical Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA
| | - E Pando
- Universitat Autónoma de Barcelona, Barcelona, Spain; Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - E Moltzer
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - E F Kauffman
- Division of General and Transplant Surgery, University of Pisa, Pisa, Italy
| | - E Warren
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA
| | - E Bozkurt
- Department of General Surgery, Koç University School of Medicine, Istanbul, Turkey
| | - E Sparrelid
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - E Thoma
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
| | - E Verkolf
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - F Ausania
- Hepatobiliopancreatic Department, Hospital Clinic de Barcelona, Barcelona, Spain; Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - F Giannone
- Department of Visceral and Digestive Surgery, University Hospital of Strasbourg, Strasbourg, France
| | - F J Hüttner
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
| | - F Burdio
- Department of Surgery, Hepatobiliary and Pancreatic Unit, Hospital del Mar de Barcelona, Barcelona, Spain; Hospital del Mar Research Institute (IMIM), University Pompeu-Fabra, Barcelona, Spain
| | - F R Souche
- Oncologic & Minimally-Invasive Digestive Surgery, CHU Montpellier, University of Montpellier, Montpellier, France
| | - F Berrevoet
- Department of General and HPB Surgery and Liver Transplantation, Ghent University Hospital, Ghent, Belgium
| | - F Daams
- Cancer Center Amsterdam, Amsterdam, The Netherlands; Amsterdam UMC, Location Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands
| | - F Motoi
- Department of Surgery, Yamagata University, Yamagata, Japan
| | - G Saliba
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - G Kazemier
- Cancer Center Amsterdam, Amsterdam, The Netherlands; Amsterdam UMC, Location Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands
| | - G Roeyen
- Department of HPB, Endocrine and Transplantation Surgery, University Hospital Antwerp, Antwerp, Belgium
| | - G Nappo
- Humanitas University, Department of Biomedical Sciences, Milan, Italy; Pancreatic Surgery Unit, Humanitas Clinical and Research Center, IRCCS, Milan, Italy
| | - G Butturini
- Department of HPB Surgery, Pederzoli Hospital, Peschiera del Garda, Peschiera, Italy
| | - G Ferrari
- Division of Minimally-Invasive Surgical Oncology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - G Kito Fusai
- HPB & Liver Transplant Unit, Royal Free Hospital, London, UK
| | - G Honda
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - G Sergeant
- Department of Abdominal Surgery, Jessa Hospital, Faculty of Medicine and Health Sciences, Universiteit Hasselt, Hasselt, Belgium
| | - H Karteszi
- Department of Radiology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - H Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University, Nagoya, Japan
| | - H Suto
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - I Matsumoto
- Department of Surgery, Kindai University, Osakasayama, Japan
| | - I Mora-Oliver
- Department of Surgery, Liver and Pancreato-Biliary Unit, Hospital Clínico Universitario Valencia, Biomedical Research Institute, INCLIVA, Valencia, Spain
| | - I Frigerio
- Department of HPB Surgery, Pederzoli Hospital, Peschiera del Garda, Peschiera, Italy
| | - J M Fabre
- Oncologic & Minimally-Invasive Digestive Surgery, CHU Montpellier, University of Montpellier, Montpellier, France
| | - J Chen
- Department of Surgery, Flinders Medical Centre, Adelaide, Australia
| | - J G Sham
- Department of Surgery, University of Washington, Seattle, USA; Fred Hutchinson Cancer Center, Seattle, USA
| | - J Davide
- HEBIPA Surgery, Centro Hospitalar Universitário de Santo António, Porto, Portugal
| | - J Urdzik
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - J de Martino
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
| | - K Nielsen
- Department of Hepatopancreatobiliary Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - K Okano
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - K Kamei
- Department of Surgery, Kindai University, Osakasayama, Japan
| | - K Okada
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - K Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Hokkaido, Japan
| | - K J Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - K E Goodsell
- Department of Surgery, University of Washington, Seattle, USA
| | - L Alberici
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - L Webber
- Department of Upper GI Surgery, Fiona Stanley Hospital, Perth, Austria
| | - L Kirkov
- Oncologic & Minimally-Invasive Digestive Surgery, CHU Montpellier, University of Montpellier, Montpellier, France
| | - L de Franco
- General and Emergency Surgery Unit, Misericordia Hospital, Azienda USL Toscana Sud-Est, Grosseto, Italy
| | - M Miyashita
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - M Maglione
- Department of Visceral, Transplant, and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - M Gramellini
- Humanitas University, Department of Biomedical Sciences, Milan, Italy; Pancreatic Surgery Unit, Humanitas Clinical and Research Center, IRCCS, Milan, Italy
| | - M Ramera
- Department of Surgery, Fondazione Poliambulanza, Instituto Ospedaliero, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - M J Amaral
- General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - M Ramaekers
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - M J Truty
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, USA
| | - M A van Dam
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - M W J Stommel
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M Petrikowski
- Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - M Imamura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Hokkaido, Japan
| | - M Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University, Nagoya, Japan
| | - M D'Hondt
- Department of Digestive and Hepatobiliary-Pancreatic Surgery, Groeninge Hospital, Kortrijk, Belgium
| | - M Brunner
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen Nürnberg, Erlangen, Germany
| | - M E Hogg
- Department of Surgery, NorthShore University Health System, Evanston, USA
| | - C Zhang
- Department of Surgery, University of Nebraska Medical Center, Omaha, USA
| | - M Á Suárez-Muñoz
- HPB Surgical Unit, University Hospital Virgen de la Victoria, Málaga, Spain
| | - M D Luyer
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - M Unno
- Department of Surgery, Tohoku University, Sendai, Japan
| | - M Mizuma
- Department of Surgery, Tohoku University, Sendai, Japan
| | - M Janot
- Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - M A Sahakyan
- The Intervention Center, Oslo University Hospital, Rigshospitalet, Oslo, Norway
| | - N B Jamieson
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - O R Busch
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - O Bilge
- Department of General Surgery, Koç University School of Medicine, Istanbul, Turkey
| | - O Belyaev
- Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - O Franklin
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA; Department of Surgery, Umeå University, Umeå, Sweden
| | - P Sánchez-Velázquez
- Department of Surgery, Hepatobiliary and Pancreatic Unit, Hospital del Mar de Barcelona, Barcelona, Spain; Hospital del Mar Research Institute (IMIM), University Pompeu-Fabra, Barcelona, Spain
| | - P Pessaux
- Department of Visceral and Digestive Surgery, University Hospital of Strasbourg, Strasbourg, France
| | - P S Holka
- Department of Clinical Sciences Lund, Surgery, Lund University, Skåne University Hospital, Lund, Sweden
| | - P Ghorbani
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - R Casadei
- Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy; Division of Pancreatic Surgery, IRCCS, Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
| | - R Sartoris
- Department of Radiology, APHP Beaujon Hospital, University of Paris Cité, Clichy, France
| | - R D Schulick
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA
| | - R Grützmann
- The Intervention Center, Oslo University Hospital, Rigshospitalet, Oslo, Norway
| | - R Sutcliffe
- Department of Hepatopancreatobiliary Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - R Mata
- Universitat Autónoma de Barcelona, Barcelona, Spain; Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - R B Patel
- Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, USA
| | - R Takahashi
- Department of Surgery, Yamagata University, Yamagata, Japan
| | - S Rodriguez Franco
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA
| | - S S Cabús
- Department of HPB Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - S Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Hokkaido, Japan
| | - S Gaujoux
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
| | - S Festen
- Department of Surgery, OLVG, Amsterdam, The Netherlands
| | - S Kozono
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - S K Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA
| | - S M Chai
- Department of Anatomical Pathology, PathWest Laboratory Medicine, Perth, Australia
| | - S Yamaki
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - S van Laarhoven
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Department of HPB Surgery, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - J S D Mieog
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - T Murakami
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Hokkaido, Japan
| | - T Codjia
- Department of Digestive Surgery, Rouen University Hospital, Rouen, France
| | - T Sumiyoshi
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - T M Karsten
- Department of Surgery, OLVG, Amsterdam, The Netherlands
| | - T Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Hokkaido, Japan
| | - T Sugawara
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA; Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo
| | - U Boggi
- Division of General and Transplant Surgery, University of Pisa, Pisa, Italy
| | - V Hartman
- Department of HPB, Endocrine and Transplantation Surgery, University Hospital Antwerp, Antwerp, Belgium
| | - V E de Meijer
- Department of Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - W Bartholomä
- Department of Radiology, Linköping University, Linköping, Sweden
| | - W Kwon
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Y X Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore
| | - Y Cho
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Y Takeyama
- Department of Surgery, Kindai University, Osakasayama, Japan
| | - Y Inoue
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan
| | - Y Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Y Kawamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Y Ome
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Z Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford Radcliffe Hospitals NHS Foundation Trust, Oxford, UK
| | - K Uemura
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C L Wolfgang
- Department of Surgical Oncology, Department of Surgery, New York University Medical Center, New York, USA
| | - J Y Jang
- Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - R Padbury
- Department of Surgery, Flinders Medical Centre, Adelaide, Australia
| | - S Satoi
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA; Department of Surgery, Kansai Medical University, Osaka, Japan
| | - W Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, USA
| | - J W Wilmink
- Cancer Center Amsterdam, Amsterdam, The Netherlands; Amsterdam UMC, Location University of Amsterdam, Department of Medical Oncology, Amsterdam, The Netherlands
| | - M Abu Hilal
- Department of HPB Surgery, Pederzoli Hospital, Peschiera del Garda, Peschiera, Italy
| | - M G Besselink
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - M Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, USA
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Maekawa A, Omiya K, Oba A, Inoue Y, Hirose Y, Kobayashi K, Ono Y, Sato T, Sasaki T, Ozaka M, Matsueda K, Mise Y, Takamatsu M, Shigematsu Y, Ito H, Saiura A, Sasahira N, Takahashi Y. Clinical implications of disappearing pancreatic cancer liver metastases: Lessons from colorectal liver metastases. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109635. [PMID: 39879814 DOI: 10.1016/j.ejso.2025.109635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/27/2024] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
BACKGROUND The efficacy of local control for pancreatic cancer liver metastases (PCLM), including surgical treatment, remains controversial, with no consensus on the management and clinical significance of disappearing liver metastases (DLMs). This study aimed to evaluate the clinical implications of DLMs in treating PCLM after multi-agent chemotherapy, utilizing contrast-enhanced imaging modalities. METHODS A retrospective analysis was conducted on patients who underwent curative resection for pancreatic cancer with synchronous or metachronous liver metastases between 2014 and 2023. Surgical indications were based on our recently reported ABCD criteria (Anatomical/Biological/Conditional/Duration). Both contrast-enhanced computed tomography (CE-CT) and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) were used to monitor metastatic lesions in the liver. DLMs were defined as tumors undetected on CE-CT post-chemotherapy. RESULTS A total of 58 lesions in 29 patients with PCLM who underwent surgical resection were evaluated. Of the 13 lesions evident on CE-CT, 76.9 % (10/13) contained clinically/pathologically residual tumors. Of the 45 DLMs, 16 (35.6 %) had residual tumors. Twenty-six DLMs (57.8 %) were detected on EOB-MRI or intraoperative screening (contrast-enhanced ultrasonography and palpation), with 42.3 % (11/26) being residual tumors. Nineteen DLMs were undetectable by any modality, of which 26.3 % (5/19) were confirmed to be residual tumors with a median follow-up of 32 months. The median overall survival from initiating treatment for PCLM was 48.5 months. CONCLUSION Integrating EOB-MRI into preoperative evaluations for PCLM enhances the detection of clinically relevant DLMs. Our findings highlight the potential benefits of considering an image-guided surgical approach in selected patients.
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Affiliation(s)
- Aya Maekawa
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kojiro Omiya
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsushi Oba
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Yosuke Inoue
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuki Hirose
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kosuke Kobayashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiro Ono
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takafumi Sato
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Sasaki
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masato Ozaka
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kiyoshi Matsueda
- Department of Diagnostic Imaging, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiro Mise
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yasuyuki Shigematsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiromichi Ito
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akio Saiura
- Department of Hepatobiliary-Pancreatic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoki Sasahira
- Department of Gastroenterological Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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Liu C, Liu C, Liu GJ, Wang MM, Jiao Y, Sun YJ, Guo H, Wang L, Lu YX, Chen Y, Ding YH. BE-43547A 2 exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1. Acta Pharmacol Sin 2025; 46:1433-1444. [PMID: 39837983 PMCID: PMC12032368 DOI: 10.1038/s41401-024-01461-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025]
Abstract
Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A2 from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A2 in human pancreatic cancer cells. We showed that BE-43547A2 displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC50 values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A2 is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A2 followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A2, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.
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Affiliation(s)
- Can Liu
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300350, China
- College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Can Liu
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Guang-Ju Liu
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | | | - Yan Jiao
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Yuan-Jun Sun
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Hui Guo
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Liang Wang
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Ya-Xin Lu
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China
| | - Yue Chen
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China.
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300350, China.
| | - Ya-Hui Ding
- State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, 300350, China.
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300350, China.
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Yun WG, Kwon W, Sohn HJ, Han Y, Chae YS, Jung HS, Cho YJ, Lim CS, Yoon YS, Jang JY. Changing Clinical Meaning of Resection Margin Status According to the Treatment Paradigm and the Potential Role of Perioperative Radiotherapy for Patients with Pancreatic Ductal Adenocarcinoma: An Updated Multicenter Retrospective Cohort Study. Ann Surg Oncol 2025:10.1245/s10434-025-17389-4. [PMID: 40304947 DOI: 10.1245/s10434-025-17389-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 04/13/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Surgeons have focused on obtaining microscopically negative margins and developing perioperative treatment strategies for pancreatic head cancer. However, the clinical significance of resection margin and radiotherapy remains unclear, particularly in neoadjuvant chemotherapy (NAC) settings. Therefore, this study aimed to evaluate the prognostic impact of margin status and perioperative radiotherapy. METHODS Between 2014 and 2019, the study enrolled 307 patients with pancreatic head cancer who underwent upfront pancreaticoduodenectomy (PD) and 97 patients who underwent NAC followed by PD at three tertiary referral hospitals. The margin status was divided into a three-tier system as follows: R0-wide (tumor-free margin, ≥ 1 mm), R0-narrow (0 mm < margin < 1 mm), and R1 (margin = 0 mm). RESULTS In the upfront surgery setting, the groups were arranged in descending order of the 5-year overall survival (OS) rates as follows: R0-wide (39.1%), R0-narrow (25.6%), and R1 (12.5%). In the NAC setting, the groups also could be arranged in descending order of 5-year OS rates as follows: R0-wide (52.2%), R0-narrow (45.5%), and R1 (8.3%). However, the differences in OS between the R0-wide and R0-narrow groups did not reach statistical significance (P = 0.587), in contrast to the upfront surgery setting. In the multivariate analyses, concurrent chemo-radiotherapy after surgery was significantly associated with a decreased risk of locoregional recurrence in both treatment settings. CONCLUSIONS Obtaining a wide margin could enhance prognosis in upfront surgery settings, and obtaining only a narrow margin could be appropriate in NAC settings. In addition, adjuvant radiotherapy could be considered, particularly for patients with margin involvement.
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Affiliation(s)
- Won-Gun Yun
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Surgery, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Hee Ju Sohn
- Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
| | - Youngmin Han
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Soo Chae
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hye-Sol Jung
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Jae Cho
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chang-Sup Lim
- Department of Surgery, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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Li L, Li J, Yan A, Xiang W, Gao W, Zhu H. Temporal trends in cross-country inequalities of early-onset pancreatic cancer: a comprehensive analysis for the global burden of disease study 2021. Sci Rep 2025; 15:14835. [PMID: 40295659 PMCID: PMC12037719 DOI: 10.1038/s41598-025-93892-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 03/10/2025] [Indexed: 04/30/2025] Open
Abstract
By 2040, pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the U.S., with early-onset pancreatic cancer (EOPC) cases rising among adolescents and young adults. This study uses the global burden of disease (GBD) 2021 dataset to examine global, regional, and national EOPC trends and predicts the burden through 2050. The analysis covers EOPC burden from 1990 to 2021, focusing on age-standardized prevalence rate (ASPR), incidence rate (ASIR), mortality rate (ASMR), and disability-adjusted life years rate (ASDR). Annual percentage change (APC) and average annual percentage change (AAPC) were calculated via joinpoint regression. Clustering and frontier analysis based on the sociodemographic index (SDI) assessed the link between development levels and health outcomes. We used WHO-recommended health equity methods to quantify EOPC burden disparities and applied a Bayesian age-period-cohort (BAPC) model to project trends. In 2021, EOPC cases rose to 42,254, a 73% increase from 1990, while deaths reached 26,996, up 57%. Although ASIR, ASMR, and ASDR declined, ASPR rose (EAPC = 0.1). Central and Eastern Europe had the highest EOPC burden, with the fastest growth in Australasia (EAPC = 2.78) and Western Sub-Saharan Africa (EAPC = 2.25). Males had about double the burden of females, though female prevalence increased. The widening gap in health burden between low- and high-SDI regions is especially concerning. While EOPC currently affects high-SDI countries the most, there is a clear trend over time showing a gradual shift of EOPC burden towards low-SDI countries. By 2050, ASIR, ASPR, ASMR, and ASDR are projected to stabilize, with cases increasing until 2036, then decreasing. High-SDI countries bear a disproportionately high EOPC burden, with significant diagnostic and management challenges, particularly in Central and Eastern Europe. Rising global EOPC prevalence highlights the need to identify burden differences and risk factors across countries to develop targeted prevention and control strategies.
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Affiliation(s)
- Luohong Li
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
- State Key Laboratory of Systems Medicine for Cancer, Department of Obstetrics and Gynecology, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jiahao Li
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - An Yan
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Wei Xiang
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Wenzhe Gao
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Hongwei Zhu
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, People's Republic of China.
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Raymakers L, Passchier EM, Verdonschot MEL, Evers M, Chan C, Kuijpers KC, Raicu GM, Molenaar IQ, van Santvoort HC, Strijbis K, Intven MPW, Daamen LA, Leusen JHW, Olofsen PA. The Efficacy of Targeted Monoclonal IgA Antibodies Against Pancreatic Ductal Adenocarcinoma. Cells 2025; 14:632. [PMID: 40358156 PMCID: PMC12071589 DOI: 10.3390/cells14090632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/11/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation.
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Affiliation(s)
- Léon Raymakers
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
- Division of Imaging & Oncology, University Medical Center Utrecht Cancer Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (M.P.W.I.); (L.A.D.)
| | - Elsemieke M. Passchier
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
| | - Meggy E. L. Verdonschot
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
| | - Mitchell Evers
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
| | - Chilam Chan
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
| | - Karel C. Kuijpers
- Department of Pathology, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, St. Antonius Hospital Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands (G.M.R.)
| | - G. Mihaela Raicu
- Department of Pathology, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, St. Antonius Hospital Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands (G.M.R.)
| | - I. Quintus Molenaar
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (I.Q.M.); (H.C.v.S.)
| | - Hjalmar C. van Santvoort
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (I.Q.M.); (H.C.v.S.)
| | - Karin Strijbis
- Department of Biomolecular Health Sciences, Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands;
| | - Martijn P. W. Intven
- Division of Imaging & Oncology, University Medical Center Utrecht Cancer Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (M.P.W.I.); (L.A.D.)
| | - Lois A. Daamen
- Division of Imaging & Oncology, University Medical Center Utrecht Cancer Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (M.P.W.I.); (L.A.D.)
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (I.Q.M.); (H.C.v.S.)
| | - Jeanette H. W. Leusen
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
| | - Patricia A. Olofsen
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (L.R.); (E.M.P.); (M.E.L.V.); (M.E.); (P.A.O.)
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Auwercx J, Neve B, Vanlaeys A, Fourgeaud M, Bourrin-Reynard I, Souidi M, Brassart-Pasco S, Hague F, Guenin S, Duchene B, Gutierrez L, Destaing O, Dhennin-Duthille I, Van Seuningen I, Jonckheere N, Gautier M. The kinase domain of TRPM7 interacts with PAK1 and regulates pancreatic cancer cell epithelial-to-mesenchymal transition. Cell Death Dis 2025; 16:335. [PMID: 40274768 PMCID: PMC12022261 DOI: 10.1038/s41419-025-07665-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the main and the deadliest form of pancreatic cancer. This is a major problem of public health since it will become the second leading cause of death by cancer in the next few years, mainly due to the lack of efficient therapies. Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) protein, a cation channel fused with a serine/threonine kinase domain is overexpressed in PDAC and associated with a low survival. In this work, we aim to study the role of kinase domain on pancreatic cell fates by using a model of kinase domain deletion by CRISPR-Cas9. PANC-1 and MIA PaCa-2 PDAC cell lines were used and kinase domain was deleted by CRISPR-Cas9 strategy. Kinase domain deletion (ΔK) was validated by RT-qPCR and western blots. The effect of kinase domain deletion on channel function was studied by patch-clamp and Mn2+-quenching. The cell phenotype was studied by MTT and cell migration/invasion assays. Finally, the role of kinase domain was studied in vivo in xenografted mice. Here we show that TRPM7 kinase domain is required to maintain a mesenchymal phenotype in PDAC cells. We also demonstrated that TRPM7 and PAK1 interact in the same protein complexes. Moreover, TRPM7 kinase domain is required for carcinogenesis and cancer cell dissemination in vivo. Intriguingly, the role of TRPM7 kinase is cell specific and may depend on the KRAS oncogene mutation status. In conclusion, TRPM7 kinase domain is required to maintain a mesenchymal and aggressive phenotype in PDAC cells, and it could be a promising target against PDAC.
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Affiliation(s)
- Julie Auwercx
- Université de Picardie Jules Verne, UR-UPJV 4667, Amiens, France
| | - Bernadette Neve
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Alison Vanlaeys
- Université de Picardie Jules Verne, UR-UPJV 4667, Amiens, France
| | | | - Ingrid Bourrin-Reynard
- Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR5309, site santé, Allée des Alpes, Grenoble, France
| | - Mouloud Souidi
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | | | - Frédéric Hague
- Université de Picardie Jules Verne, UR-UPJV 4667, Amiens, France
| | - Stéphanie Guenin
- Université de Picardie Jules Verne, Centre de Ressources Régionales en Biologie Moléculaire (CRRBM), Amiens, France
| | - Belinda Duchene
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Laurent Gutierrez
- Université de Picardie Jules Verne, Centre de Ressources Régionales en Biologie Moléculaire (CRRBM), Amiens, France
| | - Olivier Destaing
- Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR5309, site santé, Allée des Alpes, Grenoble, France
| | | | - Isabelle Van Seuningen
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Nicolas Jonckheere
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Mathieu Gautier
- Université de Picardie Jules Verne, UR-UPJV 4667, Amiens, France.
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Wilcox S, Sengupta S, Huang C, Tokuda J, Lu A, Woodrum D, Chen Y. Development of a Low-Profile, Piezoelectric Robot for MR-Guided Abdominal Needle Interventions. Ann Biomed Eng 2025:10.1007/s10439-025-03719-w. [PMID: 40266438 DOI: 10.1007/s10439-025-03719-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/25/2025] [Indexed: 04/24/2025]
Abstract
PURPOSE Minimally invasive needle-based interventions are commonly used in cancer diagnosis and treatment, including procedures, such as biopsy, brachytherapy, and microwave ablation. Although MR-guided needle placement offers several distinct advantages, such as high-resolution target visualization and accurate device tracking, one of the primary limitations that affect its widespread adoption is the ergonomic constraints of the closed-bore MRI environment, requiring the patients to be frequently moved in and out to perform the needle-based procedures. This paper introduces a low-profile, body-mounted, MR-guided robot designed to address this limitation by streamlining the operation workflow and enabling accurate needle placement within the MRI scanner. METHODS The robot employs piezoelectric linear actuators and stacked Cartesian XY stages to precisely control the position and orientation of a needle guide. A kinematic model and control framework was developed to facilitate accurate targeting. Additionally, clinical workflow for the liver interventions was developed to demonstrate the robot's capability to replicate existing procedures. The proposed system was validated in benchtop environment and 3T MRI scanner to quantify the system performance. RESULTS Experimental validations conducted in free space demonstrated a position accuracy of 2.38 ± 0.94 mm and orientation error of 1.40 ± 2.89°. Additional tests to confirm MR-conditionality and MR-guided phantom placements were carried out to assess the system's performance and safety in MRI suite, yielding a position error of 2.01 ± 0.77 mm and an orientation error of 1.57 ± 1.31°. CONCLUSION The presented robot shows exceptional compatibility with a wide range of patients and bore sizes while maintaining clinically significant accuracy. Future work will focus on the validations in dynamic liver environments.
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Affiliation(s)
- Samuel Wilcox
- Institute of Robotics and Intelligent Machines, Georgia Institute of Technology, Atlanta, GA, 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, GA, 30332, USA
| | - Saikat Sengupta
- Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Chuan Huang
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, 30322, USA
| | - Junichi Tokuda
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Aiming Lu
- Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - David Woodrum
- Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Yue Chen
- Institute of Robotics and Intelligent Machines, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
- Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, GA, 30332, USA.
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50
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Pei G, Min J, Rajapakshe KI, Branchi V, Liu Y, Selvanesan BC, Thege F, Sadeghian D, Zhang D, Cho KS, Chu Y, Dai E, Han G, Li M, Yee C, Takahashi K, Garg B, Tiriac H, Bernard V, Semaan A, Grem JL, Caffrey TC, Burks JK, Lowy AM, Aguirre AJ, Grandgenett PM, Hollingsworth MA, Guerrero PA, Wang L, Maitra A. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature 2025:10.1038/s41586-025-08927-x. [PMID: 40269162 DOI: 10.1038/s41586-025-08927-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 03/20/2025] [Indexed: 04/25/2025]
Abstract
Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1-3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive 'basal-like' cancer cells, but not to cells in the 'classical' or 'intermediate' states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4-CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.
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Affiliation(s)
- Guangsheng Pei
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jimin Min
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kimal I Rajapakshe
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vittorio Branchi
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yunhe Liu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Benson Chellakkan Selvanesan
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fredrik Thege
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dorsay Sadeghian
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daiwei Zhang
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Kyung Serk Cho
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yanshuo Chu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Enyu Dai
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guangchun Han
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mingyao Li
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Cassian Yee
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kazuki Takahashi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Bharti Garg
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Herve Tiriac
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Vincent Bernard
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander Semaan
- Department of Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jean L Grem
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Thomas C Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jared K Burks
- Department of Leukemia and Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew M Lowy
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paola A Guerrero
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Linghua Wang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
- James P. Allison Institute, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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