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Li L, Lan Z, Qiao H, Meng X, Shi Z, Zhang W, Wang Y, Sun Z, Cui Q, Wang L, Zhou S, Hu F, Zhang D, Dai Y, Chen H, Geng Y. Design of NanoBiT-Nanobody-based FGL1 biosensors for early assisted diagnosis of esophageal cancer. Biomaterials 2025; 320:123286. [PMID: 40138964 DOI: 10.1016/j.biomaterials.2025.123286] [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: 12/09/2024] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
Esophageal cancer (EC) is one of the most common causes of cancer-related mortality due in part to challenges in early diagnosis. Biomarker identification is crucial for improved early screening and treatment strategies for patients. Firstly, we employed serum proteomics techniques to screen for potential biomarkers in 15 early-stage EC patients and 5 healthy individuals. Among the differentially expressed proteins, FGL1 emerged as a promising candidate (AUC = 0.974) for early detection of EC. Subsequently, we developed NanoBiT-conjugated dual nanobodies (NBNB) sensors for robust and quantitative signal detection in fetal bovine serum (FBS) in 30 min or less, with a limit of detection (LoD) of 11.38 pM. In a case-control study recruiting 96 EC patients and 99 control samples, testing serum samples with the developed NBNB sensors revealed significantly elevated serum level of FGL1 in all-stage EC patients (AUC = 0.7880) and early-stage EC patients (AUC = 0.8286). Additionally, the combined diagnostic performance of FGL1 and CEA in EC samples is notably enhanced (AUC = 0.8847). These findings propose FGL1 as a novel and promising target for the early-stage EC diagnosis and treatment selection. Furthermore, we applied the assay to patients across six types of cancer, suggesting FGL1 as a potential pan-cancer marker. This study introduces a rapid, easy-to-use, cost-effective, reliable, universal, and high-throughput alternative to meet the growing demand for cancer biomarker testing in both academic and clinical settings.
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Affiliation(s)
- Lingyun Li
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhongyun Lan
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Huarui Qiao
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiangjing Meng
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China
| | - Ziyang Shi
- Queen Mary University of London Engineering School, Northwestern Polytechnical University, Xi'an, 710129, China
| | - Wanting Zhang
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yi'ang Wang
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zengchao Sun
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Qianqian Cui
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Lu Wang
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Siyu Zhou
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fangzheng Hu
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China.
| | - Yuanyuan Dai
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital of Chinese Academy of Medical Sciences Langfang Campus, Langfang, 065001, China.
| | - Hao Chen
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
| | - Yong Geng
- State Key Laboratory of Drug Research, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
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Umemoto K, Nakamura T, Sasaki K, Sato O, Suzuki T, Hirano S. Platelets and MMP‑9 contribute to esophageal cancer invasion via CD40‑CD154 interactions. Oncol Rep 2025; 54:79. [PMID: 40376974 PMCID: PMC12093935 DOI: 10.3892/or.2025.8912] [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: 10/28/2024] [Accepted: 03/17/2025] [Indexed: 05/18/2025] Open
Abstract
CD40 expression in esophageal cancer (EC) is linked to poor prognosis, although its molecular role remains unclear. The present study explored the function of CD40 in EC progression and metastasis, focusing on its interaction with CD154 and the upregulation of MMP‑9. CD40 expression was confirmed in EC cell lines using quantitative PCR, western blotting, flow cytometry and immunocytochemistry. Functional assays showed that recombinant soluble CD154 stimulation enhanced the migration and invasion of CD40‑overexpressing EC cells without affecting viability. Co‑culture experiments with platelets demonstrated that platelet‑derived CD154 acted on CD40‑overexpressing esophageal cancer cells, leading to upregulation of MMP‑9 secretion, potentially driving tumor invasiveness. Serum analysis of patients who underwent esophagectomy revealed that low MMP‑9 levels were associated with longer survival in pathological Stage I, whereas the opposite trend was observed in stages II‑IV. These findings indicated that CD40 activation enhanced tumor cell invasiveness through MMP‑9 upregulation. This dual role of CD40, enhancing antitumor immunity via its expression on antigen‑presenting cells, while promoting tumor invasiveness through MMP‑9 secretion when expressed on esophageal cancer cells, may complicate immunotherapeutic strategies targeting CD40, as such interventions could inadvertently promote malignancy within the tumor microenvironment.
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Affiliation(s)
- Kazufumi Umemoto
- Department of Gastroenterological Surgery II, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Katsunori Sasaki
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Osamu Sato
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Tomohiro Suzuki
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
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Li K, Chen J, Li W, Zhang Z, Xue Y, Zheng Y, Zhang Y, Zhang C, Bergan R, Zhao L. KBU2046 exerts inhibition on chemokine gradient-mediated motility of esophageal squamous cell carcinoma through reducing integrin expression. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167800. [PMID: 40118292 DOI: 10.1016/j.bbadis.2025.167800] [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: 10/15/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/23/2025]
Abstract
Esophageal squamous cell carcinoma (ESCC) cells migrate from their initial site of origin, ultimately forming metastasis and causing death. The selective inhibition of ESCC cell movement has not been possible to date. Here we demonstrate that the small molecule therapeutic agent KBU2046 inhibits the characteristic migration and invasion of ESCC cells induced by chemokine gradients, having no effect on cell proliferation. After demonstrating that KBU2046 inhibits human ESCC metastasis in a murine model, we showed that it doesn't inhibit the in vitro efficacy of chemotherapeutic agents used clinically, going on to demonstrate maintenance of cisplatin efficacy when combined with KBU2046 in a murine model. Mechanistic studies demonstrated that KBU2046 inhibited epidermal growth factor (EGF)-mediated phosphorylation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) on its Ser166 activation motif. RIPK1 was shown to be necessary for KBU2046 efficacy. However, this was shown to be dependent upon cell context, and was also shown to be dependent upon level of RIPK1 expression, both supporting the presence of additional therapeutically sensitive regulatory pathways. Mass spectrometry analysis of ESCC cells demonstrated that KBU2046 selectively altered the expression of proteins involved in cell motility. Integrin αV (ITGAV) is overexpressed in ESCC, was decreased by KBU2046, and its knockdown inhibited ESCC cell migration and invasion, which was necessary for KBU2046 efficacy. We demonstrate that ESCC's motility can be inhibited, and KBU2046 inhibits motility in an Integrin αV-dependent manner, and that combining anti-motility and cytotoxic agents is a high valuable therapeutic strategy for ESCC that should be further developed.
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Affiliation(s)
- Kexin Li
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China
| | - Jinxia Chen
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China
| | - Wendi Li
- Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Zhenzhen Zhang
- Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Yongxian Xue
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China
| | - Yang Zheng
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China
| | - Ying Zhang
- Department of Pathology, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Cong Zhang
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China
| | - Raymond Bergan
- Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, United States.
| | - Lianmei Zhao
- Research center, The Key Laboratory of Tumor Gene Diagnosis and Treatment, the Fourth Hospital of Hebei University, Shijiazhuang 050011, China; Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239, United States.
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Huang M, Wang W, Wang R, Tian R. The prognostic value of pretreatment [ 18F]FDG PET/CT parameters in esophageal cancer: a meta-analysis. Eur Radiol 2025; 35:3396-3408. [PMID: 39570366 DOI: 10.1007/s00330-024-11207-3] [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: 06/20/2024] [Revised: 08/19/2024] [Accepted: 10/14/2024] [Indexed: 11/22/2024]
Abstract
OBJECTIVES This study aims to evaluate the prognostic implications of pretreatment [18F]FDG-PET metrics in esophageal cancer patients through a meta-analysis of the existing literature. METHODS We carefully searched electronic databases, including PubMed and Embase, from inception to April 1, 2024, to identify studies describing the prognostic value of pretreatment PET metrics for advanced esophageal cancer. Clinical endpoints examined were overall survival (OS), recurrence-free survival (RFS)/disease-free survival (DFS), and progression-free survival (PFS). Hazard ratios (HRs) for PFS and OS were taken directly from the original reports. RESULTS Forty-seven publications, including 5504 patients, were included in our analysis. OS and PFS were analyzed in 31 and nine studies, respectively, and DFS/RFS was analyzed in 16 studies. The comprehensive pooled analysis revealed significant associations between metabolic parameters derived from positron emission tomography (PET) imaging and clinical outcomes. Expressly, the pooled HR indicated that patients with higher SUVmax were significantly associated with poor PFS (HR: 1.06; 95% CI: 1.01-1.12, p = 0.011) and poor RFS/DFS (HR: 1.09; 95% CI: 1.02-1.18, p = 0.019). Patients with higher SUVmean were significantly associated with poorer OS (HR: 1.07; 95% CI: 1.01-1.14, p = 0.025). High MTV was significantly associated with inferior OS (HR: 1.02; 95% CI: 1.00-1.05, p = 0.049). High TLG was significantly associated with poorer RFS/DFS (HR: 2.02; 95% CI: 1.11-3.68, p = 0.022). CONCLUSION This study unveiled pretreatment FDG-derived parameters as valuable prognostic indicators in assessing esophageal cancer outcomes. Specifically, SUVmax is associated with PFS and RFS/DFS. SUVmean and MTV were correlated with OS, and TLG was only associated with RFS/DFS. KEY POINTS Question Inconsistent findings on the prognostic value of pretreatment [18F]FDG PET parameters in esophageal cancer require comprehensive analysis to clarify their role in outcome prediction. Findings Higher pretreatment [18F]FDG-PET metrics (SUVmax, SUVmean, MTV, TLG) are associated with poor survival outcomes, emphasizing their potential value in enhancing prognostic assessments for esophageal cancer. Clinical relevance This study highlights the prognostic significance of pretreatment [18F]FDG-PET metrics in esophageal cancer, providing valuable insights for patient outcome prediction and potentially guiding personalized treatment strategies.
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Affiliation(s)
- Mingxing Huang
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Weichen Wang
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Rang Wang
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Rong Tian
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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Yu F, Gong Z, Li Y, Naseem DF, Li C, Wen M, Zhao B, Xu Z, Zhang S, Zang R, Wu A, Han Q, Wu S, Li H, Song Y. Association of SIRT6 Expression With Risk of Pneumonitis Induced by Radiotherapy in Cancer Patients. Mol Carcinog 2025; 64:1104-1118. [PMID: 40170513 PMCID: PMC12074565 DOI: 10.1002/mc.23900] [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: 01/07/2025] [Revised: 02/06/2025] [Accepted: 02/18/2025] [Indexed: 04/03/2025]
Abstract
Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.
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Affiliation(s)
- Fengyuan Yu
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zheng Gong
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Yuan Li
- Department of RadiologyAffiliated Hospital of Nanjing University of Chinese MedicineNanjingPR China
| | - Danial F. Naseem
- Department of Head and Neck SurgeryMD Anderson Cancer CenterHoustonTexasUSA
| | - Chen Li
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Miaowei Wen
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Bingying Zhao
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zhezhe Xu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shanshan Zhang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Rukun Zang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Ailu Wu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Qingxin Han
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shuhui Wu
- Department of OtorhinolaryngologyBaoshan Hospital Affiliated with Shanghai University of Traditional Chinese MedicineShanghaiPR China
| | - Hongwei Li
- Department of RadiotherapyQingdao UniversityQingdaoChina
| | - Yipeng Song
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
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Zhang SM, Sun J, Pan XO, Zhu WC, Zhou YK. Toxicity of dose-escalated, hypofractionated helical tomotherapy for inoperable thoracic esophageal squamous cell carcinoma. World J Clin Oncol 2025; 16:101378. [DOI: 10.5306/wjco.v16.i5.101378] [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: 09/12/2024] [Revised: 02/19/2025] [Accepted: 03/31/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Radiation therapy is an important treatment for esophageal tumors. However, there is still controversy regarding the total dose and fraction dose. The optimal dose and fractionation schedule have not yet been clearly established. Hypofractionated radiotherapy is becoming more popular, but it is unknown whether this is the optimal choice for esophageal tumors. In addition, the appropriate dose per fraction is uncertain. We performed a retrospective study to address these issues.
AIM To report the cumulative survival and toxicity associated with the delivered dose escalation and hypofractionation schedule of radiation therapy for esophageal squamous cell carcinoma.
METHODS Forty-seven patients treated for inoperable locally advanced thoracic esophageal squamous cell carcinoma with helical tomotherapy using different total doses and doses per fraction were enrolled. Toxicity and adverse events were evaluated in all patients to determine the acute and long-term effects according to the Toxicity Criteria of The Radiation Therapy Oncology Group. Overall survival was calculated using the Kaplan-Meier method. Logistic analysis was used to identify the correlation between dose delivered to the primary tumor and the degree of toxicity. In multivariate analysis, all variables were entered in a single step using the method of backward stepwise regression.
RESULTS Six patients died of bleeding related to aorto-esophageal fistulization. Four patients died of tracheo-esophageal fistulas, and 7 patients died of local recurrence. The remaining 20 patients died of metastases and multi-organ failure due to organ metastases. The dose of radiation and the dose level were positively correlated with esophageal toxicity, which was much greater with dose escalation and dose level per fraction increase.
CONCLUSION Esophageal toxicity can be tolerated below a prescribed radiation dose of 60 Gy and less than 2.3 Gy per fraction.
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Affiliation(s)
- Shu-Min Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jing Sun
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiang-Ou Pan
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wen-Chao Zhu
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yong-Kang Zhou
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Zhang X, Kang H, Li B, Xiong Y, Zheng S, Zhang D, Liu Y, Li S, Liu Y, Liu H, Gao Y, Ma L. Structural Optimization of 1,3-Diaryl-1,2,4-triazole-Capped Histone Deacetylase 6 Inhibitors to Obtain Novel Antiesophageal Cancer Candidates. J Med Chem 2025. [PMID: 40382720 DOI: 10.1021/acs.jmedchem.4c03231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Esophageal cancer, a leading global cancer, lacks effective therapies. Inhibition of histone deacetylase 6 (HDAC6) is a promising antitumor strategy, yet its role in esophageal cancer remains underexplored. Through structural optimization of our previously developed 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors, we identified compound 38k, exhibiting remarkably enhanced HDAC6 inhibition (IC50 = 3.12 nM) and 352-fold selectivity over HDAC1. Molecular docking analysis, CETSA, and BLI confirmed its strong HDAC6 binding. Moreover, 38k displayed robust in vitro and in vivo antiesophageal cancer efficacy, along with an advantageous pharmacokinetic and safety profile. Notably, combining 38k with a PI3K inhibitor synergistically enhanced the efficacy (75.02% tumor growth inhibition vs 50.94% monotherapy), likely by counteracting HDAC6 inhibition-induced PI3K/AKT activation. These findings validate HDAC6 as a therapeutic target and highlight 38k as a promising candidate for esophageal cancer treatment, particularly in combination regimens.
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Affiliation(s)
- Xinhui Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
- Newland Pharmaceutical Co., Ltd., Xuchang, Henan 461500, China
| | - Huiqin Kang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Bingqian Li
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Yuhan Xiong
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Shuxian Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Di Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Yuanfan Liu
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Shiyu Li
- School of Biological Engineering, Henan University of Technology, Zhengzhou, Henan 450001, China
| | - Ying Liu
- The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan 450001, China
| | - Hongmin Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Liying Ma
- State Key Laboratory of Esophageal Cancer Prevention & Treatment; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province; Institute of Drug Discovery and Development; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
- Key Laboratory of Cardio-cerebrovascular Drug, China Meheco Topfond Pharmaceutical Co., Zhumadian 463000, China
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Chen D, Zhao Z, Hong R, Yang D, Gong Y, Wu Q, Wang Y, Cao Y, Chen J, Tai Y, Liu H, Li J, Fan J, Zhang W, Song Y, Zhan Q. Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy. Nat Commun 2025; 16:4128. [PMID: 40319089 PMCID: PMC12049493 DOI: 10.1038/s41467-025-59318-9] [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: 08/15/2024] [Accepted: 04/17/2025] [Indexed: 05/07/2025] Open
Abstract
The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.
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Affiliation(s)
- Dongshao Chen
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Zitong Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoxi Hong
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Di Yang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying Gong
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Qingnan Wu
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Wang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yiren Cao
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Chen
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yidi Tai
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Haoyu Liu
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jinting Li
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiawen Fan
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Weimin Zhang
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.
| | - Yongmei Song
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Qimin Zhan
- State Key Laboratory of Molecular Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China.
- International Cancer Institute, Peking University Health Science Center, Beijing, China.
- Soochow University Cancer institute, Suzhou, Jiangsu, China.
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9
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Xiao H, Zhou T, Yang Y, Yang X, Bi Y, Cheng X. LncRNA-DANCR Promotes ESCC Progression and Function as ceRNA to Regulate DDIT3 Expression by Sponging microRNA-3193. Cancer Sci 2025; 116:1324-1338. [PMID: 40071783 PMCID: PMC12044675 DOI: 10.1111/cas.70035] [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: 10/22/2024] [Revised: 02/13/2025] [Accepted: 02/22/2025] [Indexed: 05/02/2025] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer development and progression. Among them, Differentiation Antagonizing Non-Protein Coding RNA (DANCR) has been implicated in various malignancies, including esophageal squamous cell carcinoma (ESCC). This study explores the clinical characteristics, prognostic implications, functional roles, and molecular mechanisms of DANCR in ESCC. Our results demonstrate that DANCR is highly expressed in ESCC, and acts as an oncogene in ESCC both in vitro and in vivo. Through bioinformatics analysis and experimental validation, we revealed that DANCR promotes ESCC progression by sponging miR-3193 and regulating its target gene DDIT3 expression. These findings highlight the critical role of DANCR in the development of ESCC and suggest its potential as a prognostic predictor and drug therapeutic target.
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Affiliation(s)
- Heng Xiao
- Translational Medicine Research Center, Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal CancerShanxi Medical UniversityTaiyuanShanxiChina
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of PathologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Tong Zhou
- Shanxi Academy of Medical ScienceShanxi Medical UniversityTaiyuanChina
| | - Yanfang Yang
- Translational Medicine Research Center, Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal CancerShanxi Medical UniversityTaiyuanShanxiChina
- The School of Public HealthBaotou Medical CollegeBaotouInner MongoliaChina
| | - Xin Yang
- Translational Medicine Research Center, Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal CancerShanxi Medical UniversityTaiyuanShanxiChina
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of PathologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Yanghui Bi
- Center of Gene Sequencing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuanChina
| | - Xiaolong Cheng
- Translational Medicine Research Center, Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research of Esophageal CancerShanxi Medical UniversityTaiyuanShanxiChina
- Key Laboratory of Cellular Physiology of the Ministry of Education, Department of PathologyShanxi Medical UniversityTaiyuanShanxiChina
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10
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Yin X, Cui Y, Liu T, Li Z, Liu H, Ma X, Sha X, Ma C, Han D, Yin Y. Development and validation a radiomics combined clinical model predicts treatment response for esophageal squamous cell carcinoma patients. BMC Gastroenterol 2025; 25:313. [PMID: 40301780 PMCID: PMC12042612 DOI: 10.1186/s12876-025-03899-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 04/15/2025] [Indexed: 05/01/2025] Open
Abstract
PURPOSE This study is aimed to develop and validate a machine learning model, which combined radiomics and clinical characteristics to predicting the definitive chemoradiotherapy (dCRT) treatment response in esophageal squamous cell carcinoma (ESCC) patients. METHODS 204 advanced ESCC patients were included who underwent dCRT at our hospital. Patients were randomly divided into training cohort and validation cohort with a ratio of 7:3. The radiomics features were selected by LASSO algorithm. The clinical features were selected by multivariate logistics analysis (p < 0.05). Subsequently, a combined radiomics and clinical model was established and validated to predict the treatment response in ESCC patients by logistic regression model. The performance of the model was evaluated by receiver operating characteristic (ROC) curve, decision curve analysis (DCA), nomogram, and calibration curve. RESULTS Total of 944 radiomics features were extracted from the pre-treatment contrasted enhanced CT images (CECT). After feature selection, 3 radiomics features and 3 clinical features were identified as the most predictive variables. The combined model shows better prediction performance among radiomics model or clinical model. The radiomics model's AUC values in training and validation cohort are 0.71,0.69. As for clinical model the AUC values were 0.74,0.75 in training and validation cohort. However, the AUC values in combined model are 0.79, 0.78 in training cohort and validation cohort, respectively. DCA and calibration curve also demonstrated good performance for the combined model. CONCLUSION The radiomics combined clinical features model demonstrates superior treatment response prediction ability for ESCC patients received dCRT. This model has the potential to assist clinicians in identifying non-responsive patients before treatment and guide individualized therapy for advanced ESCC patients.
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Affiliation(s)
- Xiaoyan Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Yongbin Cui
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Tonghai Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Zhenjiang Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Huiling Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital, The Third Affiliated Teaching Hospital of Xinjiang Medical University, Urumuqi, China
| | - Xingmin Ma
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Xue Sha
- Department of Radiation Oncology, Affiliated Cancer Hospital, The Third Affiliated Teaching Hospital of Xinjiang Medical University, Urumuqi, China
| | - Changsheng Ma
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Dali Han
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China
| | - Yong Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China.
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11
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Pan Y, Sun Y, Xiao Y, Ding J, Hu G, Lin Z, Chen C. DOCK9 as a predictive biomarker linked to angiogenesis and immune response in esophageal squamous cell carcinoma. Clin Exp Med 2025; 25:126. [PMID: 40272582 PMCID: PMC12021961 DOI: 10.1007/s10238-025-01653-8] [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: 12/14/2024] [Accepted: 03/26/2025] [Indexed: 04/25/2025]
Abstract
Esophageal squamous cell carcinoma (ESCC) remains a serious health concern due to its high prevalence and mortality rates. Identifying prognostic biomarkers is essential to improving patient outcomes and treatment strategies. DOCK9, a gene implicated in various cellular functions, may play a significant role in ESCC progression and prognosis. We analyzed RNA microarray datasets and single-cell RNA sequencing data to identify survival-associated genes in ESCC. Using protein expression analysis, we examined DOCK9 in ESCC tissues and assessed its functional impact on human umbilical vein endothelial cells to understand its role in angiogenesis. Additionally, we developed a 21-gene prognostic risk model, focusing on the relevance of DOCK9. Our findings revealed that DOCK9 expression is significantly reduced in ESCC tissues and correlates with poor survival outcomes. Functionally, DOCK9 was found to regulate angiogenesis and modulate the tumor-associated fibroblast environment in ESCC. Furthermore, the DOCK9/CD31 ratio emerged as a potential marker to predict immune therapy response in ESCC. DOCK9 serves as a prognostic biomarker in ESCC, influencing both angiogenesis and immune response, and could guide future therapeutic strategies, particularly in immunotherapy. This study highlights DOCK9's relevance in ESCC prognosis, supporting its potential role in tailored therapies aimed at angiogenesis and immune modulation.
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Affiliation(s)
- Yaqiang Pan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, People's Republic of China
| | - Yangyong Sun
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Ying Xiao
- Department of Emergency, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing, 211100, Jiangsu, People's Republic of China
| | - Jifei Ding
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Ge Hu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Zhiqiang Lin
- Department of Otolaryngology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China.
| | - Chang Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, People's Republic of China.
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People's Republic of China.
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12
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Zheng HT, Wang CY, Luo J, Wu YH, Ge QY, Cong ZZ, Shen Y. Endoscopic treatment versus surgical treatment for T1b esophageal cancer: a systematic review and meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110094. [PMID: 40306193 DOI: 10.1016/j.ejso.2025.110094] [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: 11/11/2024] [Revised: 03/16/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Endoscopic and surgical treatment are the two most common treatment strategies for resectable esophageal cancer (EC), but the optimal treatment for T1b EC remains controversial. This study aims to compare the efficacy and safety of endoscopic treatment versus esophagectomy for T1b EC. METHODS Web of Science, MEDLINE, Scopus, and EMBASE were searched from their inception to December 2023. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, we used the fixed- and random-effect models for this meta-analysis by RevMan. The primary outcomes included overall survival (OS), recurrence, lymph node metastasis, complete resection rate and positive resection margin. The secondary outcomes were 1-year survival, 3-year survival, 5-year survival, overall mortality rate, EC-specific mortality rate and lymphovascular invasion. RESULTS Nine studies with a population of 1637 patients (endoscopic treatment: 715 patients; surgical treatment: 922 patients) were included. The pooled results showed that surgical treatment was associated with a significantly better OS than endoscopic treatment (Hazard Ratio [HR] = 0.78; 95 % confidence interval [CI]: [0.62, 1.00]; P = 0.05). There was also significant difference in positive resection margin (Relative Risk [RR] = 0.13; 95 % CI: [0.09, 0.20]; P < 0.00001) between the two treatment strategies. CONCLUSION The pooled results of this study indicated that surgical treatment had better OS than endoscopic treatment for T1b EC. Furthermore, endoscopic treatment also had significantly higher risk of margin positivity than surgical treatment for T1b EC.
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Affiliation(s)
- Hao-Tian Zheng
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China
| | - Chang-Yong Wang
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China
| | - Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yu-Heng Wu
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qi-Yue Ge
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China.
| | - Zhuang-Zhuang Cong
- Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yi Shen
- School of Medicine, Southeast University, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Nanjing, China; Department of Cardiothoracic Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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13
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Ju Q, Sheng W, Zhang M, Chen J, Wu L, Liu X, Fang W, Shi H, Sun C. TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis. eLife 2025; 13:RP97373. [PMID: 40266671 PMCID: PMC12017773 DOI: 10.7554/elife.97373] [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] [Indexed: 04/24/2025] Open
Abstract
TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.
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Affiliation(s)
- Qianqian Ju
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
| | - Wenjing Sheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
| | - Meichen Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
| | - Jing Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
| | - Liucheng Wu
- Laboratory Animal Center, Nantong UniversityNantongChina
| | - Xiaoyu Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
| | - Wentao Fang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hui Shi
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Cheng Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products; School of Medicine, Nantong UniversityNantongChina
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14
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Wen L, Fu J, Wang Z, Xie R, Tang S, Yu L, Zhou H. Regulatory mechanisms of m6A RNA methylation in esophageal cancer: a comprehensive review. Front Genet 2025; 16:1561799. [PMID: 40330012 PMCID: PMC12053326 DOI: 10.3389/fgene.2025.1561799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/07/2025] [Indexed: 05/08/2025] Open
Abstract
Esophageal cancer is an aggressively malignant neoplasm characterized by a high mortality rate. Frequently diagnosed at an advanced stage, it presents challenges for optimal therapeutic intervention due to its non-specific symptoms, resulting in lost opportunities for effective treatment, such as surgery, radiotherapy, chemotherapy and target therapy. The N6-methyladenosine (m6A) modification represents the most critical post-transcriptional modification of eukaryotic messenger RNA (mRNA). The reversible m6A modification is mediated by three regulatory factors: m6A methyltransferases, demethylating enzymes, and m6A recognition proteins. These components identify and bind to specific RNA methylation sites, thereby modulating essential biological functions such as RNA processing, nuclear export, stability, translation and degradation, which significantly influence tumorigenesis, invasion, and metastasis. Given the importance of m6A modification, this paper offers a comprehensive examination of the regulatory mechanisms, biological functions, and future therapeutic implications of m6A RNA methylation in the context of esophageal cancer.
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Affiliation(s)
- Long Wen
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, North Sichuan Medical College, Institute of Surgery, Nanchong, China
| | - Jiang Fu
- Graduate School, Institute of Surgery, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zixu Wang
- Graduate School, Institute of Surgery, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rangping Xie
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shengjie Tang
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Li Yu
- Department of Physical Examination, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Haining Zhou
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, North Sichuan Medical College, Institute of Surgery, Nanchong, China
- Graduate School, Institute of Surgery, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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15
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Anderson C, Veitch R, Lekamalage B, Mafi D, Rossaak J, Smith B, Patel R. Ten-year review of oesophagectomy in a regional New Zealand hospital: making the case for a low-volume centre. ANZ J Surg 2025. [PMID: 40257078 DOI: 10.1111/ans.70137] [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: 11/27/2024] [Revised: 03/05/2025] [Accepted: 04/06/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND Oesophageal cancer is a highly aggressive malignancy with poor survival rates. The treatment approach is multimodal, employing endoscopy and chemoradiotherapy; however, surgical resection remains a mainstay of management. Centres with high volumes of resections are associated with improved outcomes, but an optimal number for annual caseload is not defined. International benchmarks for morbidity and mortality have been established by the Oesophageal Complications Consensus Group (ECCG) using data from high-volume centres. This study compared data from a New Zealand low-volume centre against these. METHODS This retrospective study included all patients undergoing oesophagectomy at Tauranga Hospital between 2014 and 2023, with primary analysis comparing mortality and complications to the ECCG benchmarks. Secondary analysis stratified data by age, ethnicity, comorbidity, and preoperative treatment. RESULTS Sixty-one patients underwent oesophagectomy, with a 30-day mortality of 0% and a 90-day mortality of 1.6%, both below the ECCG benchmarks. However, complication rates were higher, with anastomotic leak (16.4%) and Clavien-Dindo ≥3B complications (26.2%) exceeding the benchmark rates. There were no significant differences in outcomes stratified by demographic or clinical subgroups. CONCLUSION This study finds better mortality outcomes and poorer morbidity outcomes than the benchmark. These results suggest that low-volume centres which concurrently perform similar complex oncological resections and have access to dedicated Intensive Care, interventional radiology, and endoscopy may have comparable results to high-volume centres. If similar centres achieve good outcomes, consideration must be given to keeping regional oesophagectomy services to reduce inequities and improve access to healthcare.
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Affiliation(s)
- Cain Anderson
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
| | - Rebecca Veitch
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
| | | | - Daniel Mafi
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
| | - Jeremy Rossaak
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
| | - Barnaby Smith
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
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16
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Ren Y, Wang F, Zhu Z, Luo R, Lv G, Cui H. Breath biomarkers for esophageal cancer: identification, quantification, and diagnostic modeling. ANAL SCI 2025:10.1007/s44211-025-00769-x. [PMID: 40232623 DOI: 10.1007/s44211-025-00769-x] [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: 02/28/2025] [Accepted: 04/01/2025] [Indexed: 04/16/2025]
Abstract
Esophageal cancer is a major global health issue with a high mortality rate. Early diagnosis is crucial for improving patient outcomes, but traditional diagnostic methods are often invasive and costly. This study explores the potential of exhaled volatile organic compounds (VOCs) as a non-invasive diagnostic tool for esophageal cancer. Using gas chromatography-mass spectrometry (GC-MS), we analyzed the breath samples of 80 esophageal cancer patients and 60 healthy controls, identifying and quantifying over 100 VOCs. The results revealed significant differences in the concentrations of VOCs such as acetone, ethanol, and isoprene between the two groups. A multi-parameter regression diagnostic model based on a neural network algorithm achieved an accuracy of 90.3% in distinguishing esophageal cancer patients from healthy individuals. Further optimization incorporating physiological factors, including smoking, drinking, and dietary habits, improved the model's accuracy to 92.4%, with a specificity of 93.1%, representing a significant improvement over previous studies. These results suggest that VOCs analysis in exhaled breath holds great promise as a non-invasive, cost-effective, and accurate method for early detection of esophageal cancer.
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Affiliation(s)
- Yuke Ren
- Key Laboratory of Clean Energy and Carbon Neutrality of Zhejiang Province, State Key Laboratory of Clean Energy Utilization (Zhejiang University), Hangzhou, 310027, China
| | - Fei Wang
- Key Laboratory of Clean Energy and Carbon Neutrality of Zhejiang Province, State Key Laboratory of Clean Energy Utilization (Zhejiang University), Hangzhou, 310027, China.
| | - Ziyi Zhu
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Raojun Luo
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Guojun Lv
- Key Laboratory of Clean Energy and Carbon Neutrality of Zhejiang Province, State Key Laboratory of Clean Energy Utilization (Zhejiang University), Hangzhou, 310027, China
| | - Haibin Cui
- Key Laboratory of Clean Energy and Carbon Neutrality of Zhejiang Province, State Key Laboratory of Clean Energy Utilization (Zhejiang University), Hangzhou, 310027, China
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Tachibana S, Moriichi K, Takahashi K, Sato M, Kobayashi Y, Sugiyama Y, Sasaki T, Sakatani A, Ando K, Ueno N, Kashima S, Tanabe H, Fujiya M. Curative endoscopic submucosal dissection for esophageal squamous cell carcinoma after chemoradiotherapy for pharyngeal cancer: A case report. World J Gastrointest Oncol 2025; 17:101123. [PMID: 40235884 PMCID: PMC11995334 DOI: 10.4251/wjgo.v17.i4.101123] [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: 09/04/2024] [Revised: 01/01/2025] [Accepted: 01/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is often managed with surgery, which is the first-line treatment option for stage I-III lesions. However, definitive chemoradiotherapy (dCRT) is associated with a recurrence rate of 30% in stage I ESCC and higher rates in advanced-staged lesions. However, several patients prefer dCRT because their general condition is poor. Salvage therapies, including esophagectomy and endoscopic resection [endoscopic submucosal dissection (ESD)/endoscopic mucosal resection], are important for residual or recurrent tumors that develop after dCRT. Esophagectomy can have curative potential. However, it has high complication and mortality rates. Therefore, ESD is a safer alternative. CASE SUMMARY A Japanese man in his 70s was concurrently diagnosed with right hypopharyngeal cancer (T2N1M0, cStage III), left oropharyngeal cancer (T1N0M0, cStage I), and left hard palate cancer (T1N0M0, cStage I). Esophagogastroduodenoscopy (EGD) revealed a 20 mm reddish 0-Is+IIb lesion in the upper thoracic esophagus, with an invasion depth of SM2. The lesion was diagnosed as an esophageal moderately differentiated squamous cell carcinoma (T1bN0M0, cStage I). As the pharyngeal cancers were in advanced stages, chemoradiotherapy (docetaxel and cisplatin with a radiation dose of 66 Gy) was prioritized. Post-chemoradiotherapy EGD showed that the lesion had flattened into a 0-IIb lesion, thereby indicating a reduced invasion depth (epithelium or lamina propria mucosa). ESD achieved en bloc and histologically confirmed curative resection. At 22 months after ESD, the patient did not present with signs of recurrence. CONCLUSION This case emphasizes that ESD can be successfully utilized as a salvage treatment for ESCC after chemoradiotherapy for otolaryngological cancers.
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Affiliation(s)
- Shion Tachibana
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Kentaro Moriichi
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Keitaro Takahashi
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Masahiro Sato
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Yu Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Yuya Sugiyama
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Takahiro Sasaki
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Aki Sakatani
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Katsuyoshi Ando
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Nobuhiro Ueno
- Department of General Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Shin Kashima
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Hiroki Tanabe
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa 078-8510, Hokkaidō, Japan
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Chen S, Zhou S, Wu L, Chen S, Liu S, Li H, Ruan G, Liu L, Chen H. Incorporating frequency domain features into radiomics for improved prognosis of esophageal cancer. Med Biol Eng Comput 2025:10.1007/s11517-025-03356-4. [PMID: 40208480 DOI: 10.1007/s11517-025-03356-4] [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: 01/13/2025] [Accepted: 03/23/2025] [Indexed: 04/11/2025]
Abstract
Esophageal cancer is a highly aggressive gastrointestinal malignancy with a poor prognosis, making accurate prognostic assessment essential for patient care. The performance of the esophageal cancer prognosis model based on conventional radiomics is limited, as it mainly characterizes the spatial features such as texture of the tumor area, and cannot fully describe the complexity of esophageal cancer tumors. Therefore, we incorporate the frequency domain features into radiomics to improve the prognostic ability of esophageal cancer. Three hundred fifteen esophageal cancer patients participated in the death risk prediction experiment, with 80% being the training set and 20% being the testing set. We use fivefold cross validation for training, and fuse the 5 trained models through voting to obtain the final prognostic model for testing. The CatBoost achieved the best performance compared to machine learning methods such as random forests and decision tree. The experimental results showed that the combination of frequency domain and radiomics features achieved the highest performance in death predicting esophageal cancer (accuracy: 0.7423, precision: 0.7470, recall: 0.7375, specification: 0.8030, AUC: 0.8487), which was significantly better than the performance of frequency domain or radiomics features alone. The results of Kaplan-Meier survival analysis validated the performance of our method in death predicting esophageal cancer. The proposed method provides technical support for accurate prognosis of esophageal cancer.
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Affiliation(s)
- Shu Chen
- School of Life & Environmental Science, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Shumin Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China
| | - Liyang Wu
- School of Life & Environmental Science, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Shuchao Chen
- School of Life & Environmental Science, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Shanshan Liu
- School of Life & Environmental Science, Guilin University of Electronic Technology, Guilin, 541004, China
| | - Haojiang Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China
| | - Guangying Ruan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China
| | - Lizhi Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangdong Esophageal Cancer Institute, Guangzhou, 510060, China.
| | - Hongbo Chen
- School of Life & Environmental Science, Guilin University of Electronic Technology, Guilin, 541004, China.
- Guangxi Human Physiological Information Noninvasive Detection Engineering Technology Research Center, Guilin, 541004, China.
- Guangxi Colleges and Universities Key Laboratory of Biomedical Sensors and Intelligent Instruments, Guilin, 541004, China.
- Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, Guilin, 541004, China.
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Hosseini N, Forghanifard MM. MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma. BMC Med Genomics 2025; 18:69. [PMID: 40211274 PMCID: PMC11983858 DOI: 10.1186/s12920-025-02134-3] [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: 02/23/2025] [Accepted: 03/27/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/β-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells. MATERIALS AND METHODS Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway. RESULTS The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased. CONCLUSIONS Our data suggest that MEIS1 gene probably induces WNT/β-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.
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Affiliation(s)
- Nayyerehalsadat Hosseini
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mahdi Forghanifard
- Department of Biology, Da.C., Islamic Azad University, Cheshmeh-Ali Boulevard, Sa'dei square, P.O.Box: 3671639998, Damghan, Iran.
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20
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Yin Q, Zhang Y, Xie X, Hou M, Chen X, Ding J. Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates. Cell Death Discov 2025; 11:144. [PMID: 40188055 PMCID: PMC11972320 DOI: 10.1038/s41420-025-02429-5] [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: 11/05/2024] [Revised: 03/07/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.
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Affiliation(s)
- Qingling Yin
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Yanlong Zhang
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Xueqing Xie
- GuiZhou University Medical College, Guiyang, 550025, Guizhou, China
| | - Meijun Hou
- Graduate School, Zunyi Medical University, Zunyi, Guizhou, 563006, China
| | - Xunsheng Chen
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China
| | - Jie Ding
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guiyang, China.
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21
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Baik YS, Lee H, Kim YJ, Chung JW, Kim KG. Early detection of esophageal cancer: Evaluating AI algorithms with multi-institutional narrowband and white-light imaging data. PLoS One 2025; 20:e0321092. [PMID: 40184395 PMCID: PMC11970661 DOI: 10.1371/journal.pone.0321092] [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: 10/21/2024] [Accepted: 02/28/2025] [Indexed: 04/06/2025] Open
Abstract
Esophageal cancer is one of the most common cancers worldwide, especially esophageal squamous cell carcinoma, which is often diagnosed at a late stage and has a poor prognosis. This study aimed to develop an algorithm to detect tumors in esophageal endoscopy images using innovative artificial intelligence (AI) techniques for early diagnosis and detection of esophageal cancer. We used white light and narrowband imaging data collected from Gachon University Gil Hospital, and applied YOLOv5 and RetinaNet detection models to detect lesions. The models demonstrated high performance, with RetinaNet achieving a precision of 98.4% and sensitivity of 91.3% in the NBI dataset, and YOLOv5 attaining a precision of 93.7% and sensitivity of 89.9% in the WLI dataset. The generalizability of these models was further validated using external data from multiple institutions. This study demonstrates an effective method for detecting esophageal tumors through AI-based esophageal endoscopic image analysis. These efforts are expected to significantly reduce misdiagnosis rates, enhance the effective diagnosis and treatment of esophageal cancer, and promote the standardization of medical services.
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Affiliation(s)
- Young Seo Baik
- Department of Biomedical Engineering, Gachon University, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Hannah Lee
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Young Jae Kim
- Department of Gachon Biomedical & Convergence Institute, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Jun-Won Chung
- Division of Gastroenterology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Kwang Gi Kim
- Department of Biomedical Engineering, College of IT Convergence, Gachon University, Seongnam-si, Gyeonggi-do, Republic of Korea
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22
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Sun Y, Tang Y, Qi Q, Pang J, Chen Y, Wang H, Liang J, Tang W. 101 Machine Learning Algorithms for Mining Esophageal Squamous Cell Carcinoma Neoantigen Prognostic Models in Single-Cell Data. Int J Mol Sci 2025; 26:3373. [PMID: 40244296 PMCID: PMC11989522 DOI: 10.3390/ijms26073373] [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: 03/23/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in the digestive tract, characterized by a high recurrence rate and inadequate immunotherapy options. We analyzed mutation data of ESCC from public databases and employed 10 machine learning algorithms to generate 101 algorithm combinations. Based on the optimal range determined by the concordance index, we randomly selected one combination from the best-performing algorithms to construct a prognostic model consisting of five genes (DLX5, MAGEA4, PMEPA1, RCN1, and TIMP1). By validating the correlation between the prognostic model and antigen-presenting cells (APCs), we revealed the antigen-presentation efficacy of the model. Through the analysis of immune infiltration in ESCC, we uncovered the mechanisms of immune evasion associated with the disease. In addition, we examined the potential impact of the five prognostic genes on ESCC progression. Based on these insights, we identified anti-tumor small-molecule compounds targeting these prognostic genes. This study primarily simulates the tumor microenvironment (TME) and antigen presentation processes in ESCC patients, predicting the role of the neoantigen-based prognostic model in ESCC patients and their potential responses to immunotherapy. These results suggest a potential approach for identifying therapeutic targets in ESCC, which may contribute to the development of more effective treatment strategies.
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Affiliation(s)
| | | | | | | | | | | | | | - Wenru Tang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming 650500, China; (Y.S.); (Y.T.); (Q.Q.); (J.P.); (Y.C.); (H.W.); (J.L.)
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23
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Wang J, Li B, Zhang Y, Luo X, Zhang Y, Li H, Pan Y, Shao L, Zheng S, Yuan C, Li Y, Zheng Q, Sun S, Zhao W, Sun Y. Tislelizumab combined with nab-paclitaxel and cisplatin as the more effective chemoimmunotherapy strategy in the neoadjuvant treatment of locally advanced thoracic esophageal squamous cell carcinoma: A prospective, two-cohort, phase 2 trial. Int J Cancer 2025; 156:1429-1438. [PMID: 39686540 DOI: 10.1002/ijc.35261] [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: 06/18/2024] [Revised: 09/04/2024] [Accepted: 09/17/2024] [Indexed: 12/18/2024]
Abstract
This prospective, two-cohort phase 2 trial with random allocation was conducted to evaluate the safety and efficacy of neoadjuvant tislelizumab combined with nab-paclitaxel/paclitaxel and cisplatin (TP) in patients with esophageal squamous cell carcinoma (ESCC). Patients were enrolled and randomly assigned to the nab-paclitaxel or paclitaxel cohorts at a 1:1 ratio, and received intravenous tislelizumab (200 mg, day 1) combined with cisplatin (25 mg/m2, days 1-3) and either nab-paclitaxel (125 mg/m2, days 1 and 8) or paclitaxel (150 mg/m2, day 1) in a 21-day cycle for two cycles before surgery. The primary endpoint was the major pathological response (MPR) rate. From March 01, 2022 to April 10, 2023, 46 patients were enrolled (n = 23 in each cohort), with 42 patients receiving the full two-cycle treatments and undergoing surgery (n = 22 in the nab-paclitaxel cohort, n = 20 in the paclitaxel cohort). The MPR rate and the pCR rate in the total cohort were 44.2% (19/42) and 19.0% (8/42), respectively, with 59.1% (13/22) and 31.8% (7/22) in the nab-paclitaxel cohort and 30.0% (6/20) and 5.0% (1/20) in paclitaxel cohorts. The most common treatment-related adverse events (TRAEs) were anemia (89.1%) and alopecia (71.7%), and no significant difference in TRAEs was observed between the two cohorts. Up until March 28, 2024, the median follow-up time was 15.5 months (range of 6.0-24.3 months), and the survival analysis revealed that the patients in the nab-paclitaxel cohort had a higher event-free survival (p = .002). In conclusion, neoadjuvant tislelizumab combined with cisplatin and nab-paclitaxel, rather than cisplatin and paclitaxel, is a more effective neoadjuvant strategy for locally advanced thoracic ESCC.
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Affiliation(s)
- Jie Wang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bin Li
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yawei Zhang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyang Luo
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yiliang Zhang
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hang Li
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yunjian Pan
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Longlong Shao
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shanbo Zheng
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chongze Yuan
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuan Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qiang Zheng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Si Sun
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Weixin Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yihua Sun
- Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
- Institute of Thoracic Oncology, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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24
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Ko MT, Thomas T, Holden E, Beales ILP, Alexandre L. The Association Between Obesity and Malignant Progression of Barrett's Esophagus: A Systematic Review and Dose-Response Meta-Analysis. Clin Gastroenterol Hepatol 2025; 23:726-738.e28. [PMID: 39237080 DOI: 10.1016/j.cgh.2024.07.041] [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: 05/06/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND AND AIMS Obesity is a risk factor for both Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). However, it is unclear whether obesity drives the malignant progression of BE. We aimed to assess whether obesity is associated with high-grade dysplasia (HGD) or cancer in patients with BE. METHODS We searched MEDLINE and EMBASE from inception through April 2024 for studies reporting the effect of body mass index (BMI) on the progression of nondysplastic BE or low-grade dysplasia (LGD) to HGD or EAC. A 2-stage dose-response meta-analysis was performed to estimate the dose-response relationship between BMI with malignant progression. Study quality was appraised using a modified Newcastle-Ottawa scale. RESULTS Twenty studies reported data on 38,565 patients (74.4% male) in total, of whom 1684 patients were diagnosed with HGD/cancer. Nineteen studies were considered moderate to high quality. Eight cohort studies reported data on 6647 male patients with baseline nondysplastic BE/LGD, of whom 555 progressed to HGD/EAC (pooled annual rate of progression, 0.02%; 95% confidence interval [CI], 0.01%-0.03%), and 1992 female patients with baseline nondysplastic BE/LGD, with 110 progressors (pooled annual rate of progression, 0.01%; 95% CI, 0.01%-0.02%). There was no significant difference in pooled annual rate of progression between males and females (P = .15). Each 5-kg/m2 increase in BMI was associated with a 6% increase in the risk of malignant progression (adjusted odds ratio, 1.06; 95% CI, 1.02-1.10; P < .001; I2= 0%). CONCLUSION Our meta-analysis provides some evidence that obesity as measured by BMI is associated with malignant progression of BE with a dose-response relationship. This finding requires confirmation in future high-quality cohort studies. Future risk prediction models could incorporate measures of obesity to potentially improve risk stratification in patients with BE. PROSPERO, Number: CRD42017051046.
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Affiliation(s)
- Mie Thu Ko
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - Tom Thomas
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Emily Holden
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Ian L P Beales
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - Leo Alexandre
- Norwich Epidemiology Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; Department of Gastroenterology, Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom.
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25
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Dahiya DS, Malik S, Paladiya R, Ahsan S, Wasim H, Bharadwaj HR, Goel A, Jaan A, Hayat U, Hasan F, Sonaiya S, Ali H. Advances in Non-Invasive Screening Methods for Gastrointestinal Cancers: How Continued Innovation Has Revolutionized Early Cancer Detection. Cancers (Basel) 2025; 17:1085. [PMID: 40227568 PMCID: PMC11987734 DOI: 10.3390/cancers17071085] [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: 02/03/2025] [Revised: 02/24/2025] [Accepted: 03/22/2025] [Indexed: 04/15/2025] Open
Abstract
The early diagnosis of gastrointestinal cancers is essential for better survival and to reduce the burden of malignancies worldwide [...].
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Affiliation(s)
- Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
| | - Sheza Malik
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Ruchir Paladiya
- Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT 06269, USA
| | - Sidra Ahsan
- Department of Internal Medicine, Ochsner LSU Health—Fairfield Medical Office Building, 1801 Fairfield Ave, Shreveport, LA 71101, USA
| | - Haniya Wasim
- Department of Internal Medicine, AdventHealth West Florida, Altamonte Springs, FL 32701, USA
| | | | - Abhishek Goel
- Department of Internal Medicine, Cape Fear Valley Medical Center, Fayetteville, NC 23804, USA
| | - Ali Jaan
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Umar Hayat
- Department of Internal Medicine, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, PA 18711, USA
| | - Fariha Hasan
- Department of Internal Medicine, Cooper University Hospital, Camden, NJ 08103, USA
| | - Sneh Sonaiya
- Department of Internal Medicine, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
| | - Hassam Ali
- Division of Gastroenterology, Hepatology & Nutrition, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA
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Ahn H, Ramineni M, Shi H, Li RX, Velez M, Hao Y. Neoadjuvant Therapy-Associated CDX2 Expression and Its Prognostic Implication in Esophageal Adenocarcinoma. J Transl Med 2025; 105:104135. [PMID: 40139501 DOI: 10.1016/j.labinv.2025.104135] [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: 11/08/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
Neoadjuvant chemoradiotherapy followed by surgery is the standard care for locally advanced esophageal adenocarcinoma. However, reliable postoperative prognostic biomarkers are still needed to stratify patients with different clinical outcomes. This study aimed to investigate postneoadjuvant expression changes of CDX2 and its association with histopathological features, biomarkers for targeted therapy, distant metastasis, and survival status. A total of 62 esophagogastrectomy specimens from one institution were evaluated. A tissue microarray was constructed, and IHC staining was performed. CDX2 expression was found in 27 (43.5%) cases with well-to-poor differentiation. Compared with preoperative biopsies, 68.8% of cases demonstrated induced or enhanced CDX2 expression. There were no significant differences in age, tumor location, histologic grade, lymph node metastasis, tumor stage, and treatment response between CDX2-positive and CDX2-negative groups. Neuroendocrine and Paneth cell differentiation induced by neoadjuvant therapy were more commonly seen in CDX2-positive cases. CDX2 expression was associated with higher multidrug resistance-1 and HER-2 expression. Patients with CDX2-positive diseases showed a higher risk of distant metastasis and a worse prognosis than those with CDX2-negative diseases.
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Affiliation(s)
- Heong Ahn
- Department of Pathology and Laboratory Medicine, The University of Rochester Medical Center, Rochester, New York, New York
| | - Madhurya Ramineni
- Department of Pathology and Laboratory Medicine, The University of Rochester Medical Center, Rochester, New York, New York
| | - Hangchuan Shi
- Department of Pathology and Laboratory Medicine, The University of Rochester Medical Center, Rochester, New York, New York
| | - Rena X Li
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Moises Velez
- Department of Pathology and Laboratory Medicine, The University of Rochester Medical Center, Rochester, New York, New York
| | - Yansheng Hao
- Department of Pathology and Laboratory Medicine, The University of Rochester Medical Center, Rochester, New York, New York.
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Grothey B, Lyu SI, Quaas A, Simon AG, Jung JO, Schröder W, Bruns CJ, Schiffmann LM, Popp FC, Schmidt T, Knipper K. Proteomic characterization of MET-amplified esophageal adenocarcinomas reveals enrichment of alternative splicing- and androgen signaling-related proteins. Cell Mol Life Sci 2025; 82:112. [PMID: 40074836 PMCID: PMC11904063 DOI: 10.1007/s00018-025-05635-7] [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: 09/10/2024] [Revised: 02/11/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. METHODS In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified (n = 20) versus non-amplified tumors (n = 39) by mass spectrometry. RESULTS We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. CONCLUSIONS Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.
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Affiliation(s)
- Bastian Grothey
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Su Ir Lyu
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Adrian Georg Simon
- Faculty of Medicine, Institute of Pathology, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Jin-On Jung
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Wolfgang Schröder
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Lars M Schiffmann
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Felix C Popp
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Thomas Schmidt
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Karl Knipper
- Faculty of Medicine, Department of General, Visceral and Cancer Surgery, University Hospital of Cologne, University of Cologne, Cologne, Germany.
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Wei C, Zhang X, Li H, Gu J, Xue F, Xie W, Ji G. STMN1 regulates the stemness of gastric cancer cells by binding to HN1L to activate the STAT3 signaling pathway. Discov Oncol 2025; 16:263. [PMID: 40035993 PMCID: PMC11880488 DOI: 10.1007/s12672-025-01879-8] [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: 11/01/2024] [Accepted: 02/03/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND STMN1 is highly expressed in gastric cancer (GC) tissues and the aim of this study was to investigate the role of STMN1 in GC cell stemness. METHODS Analysis of the expression and correlation of STMN1 and its target genes in GC through bioinformatics. Construction of interference plasmids for STMN1 and transfection into GC cells. Sphere formation assay was conducted to detect stem cell sphere-forming ability. WB analysis was performed to detect the expression of stemness genes CD133, ALDH1, CD44, SOX2, Nanog, and STAT3-related proteins. Additionally, CCK-8 assay and TUNEL staining were used to assess GC cell sensitivity to cisplatin (DDP). Construction of a xenograft mouse model to detect the in vivo tumorigenic ability of GC cells. Immunoprecipitation (IP) experiment was conducted to validate the binding of STMN1 and HN1L in GC cells. Overexpression plasmids of HN1L were used for mechanism validation. RESULTS STMN1 and its target HN1L were highly expressed in GC tissues and cells, and were associated with a poor prognosis in GC. Interfering with STMN1 significantly reduced the self-renewal ability of GC cells, downregulated the expression of CD133, ALDH1, CD44, SOX2, Nanog, p-STAT3 and PD-L1. Interfering with STMN1 increased the sensitivity of GC cells to DDP and promoted apoptosis. IP experiments demonstrate that STMN1 and HN1L combine in GC cells. Overexpression of HN1L significantly reversed the effects of Si-STMN1 on GC cells. In vivo experiments demonstrate that the addition of DDP or interference with STMN1 reduced tumor size and weight, and downregulated the expression of CD133, KI67, HN1L, p-STAT3, and PD-L1 in tumor tissues. The combined use of DPP and Si-STMN1 had a more significant effect. CONCLUSION STMN1 regulates GC cell stemness by binding HN1L to activate the HN1L/STAT3/ PD-L1 signaling pathway.
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Affiliation(s)
- Chunyang Wei
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Xing Zhang
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Hao Li
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Jianzhong Gu
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Fei Xue
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Wenna Xie
- Department of Gastrointestinal Surgery, The First People's Hospital of Yinchuan, Ningxia, 750001, China
| | - Gang Ji
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air Force Me dical University, Xi'an, 710032, China.
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Yates J, Mathey-Andrews C, Park J, Garza A, Gagné A, Hoffman S, Bi K, Titchen B, Hennessey C, Remland J, Shannon E, Camp S, Balamurali S, Cavale SK, Li Z, Raghawan AK, Kraft A, Boland G, Aguirre AJ, Sethi NS, Boeva V, Van Allen E. Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.08.17.608386. [PMID: 39229240 PMCID: PMC11370330 DOI: 10.1101/2024.08.17.608386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.
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Affiliation(s)
- Josephine Yates
- Institute for Machine Learning, Department of Computer Science, ETH Zürich, Zurich, Switzerland
- ETH AI Center, ETH Zurich, Zurich, Switzerland
- Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Camille Mathey-Andrews
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jihye Park
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Amanda Garza
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Andréanne Gagné
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Samantha Hoffman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA
| | - Kevin Bi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Breanna Titchen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA
| | | | - Joshua Remland
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Erin Shannon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Sabrina Camp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Siddhi Balamurali
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Shweta Kiran Cavale
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Akhouri Kishore Raghawan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Agnieszka Kraft
- Institute for Machine Learning, Department of Computer Science, ETH Zürich, Zurich, Switzerland
- Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland
| | - Genevieve Boland
- Department of Surgery, Division of Gastrointestinal and Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Nilay S Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Valentina Boeva
- Institute for Machine Learning, Department of Computer Science, ETH Zürich, Zurich, Switzerland
- ETH AI Center, ETH Zurich, Zurich, Switzerland
- Swiss Institute for Bioinformatics (SIB), Lausanne, Switzerland
- Cochin Institute, Inserm U1016, CNRS UMR 8104, Paris Descartes University UMR-S1016, Paris 75014, France
| | - Eliezer Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA
- Parker Institute for Cancer Immunotherapy, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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Wang T, Li J, Du J, Zhou W, Lu G. Recent advances in the role of atypical cadherin FAT1 in tumorigenesis (Review). Oncol Lett 2025; 29:110. [PMID: 39776648 PMCID: PMC11704873 DOI: 10.3892/ol.2024.14856] [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: 08/17/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
The FAT atypical cadherin 1 (FAT1) gene is the ortholog of the Drosophila fat gene and encodes the protocadherin FAT1. FAT1 belongs to the cadherin superfamily, a group of full-length membrane proteins that contain cadherin-like repeats. In various types of human cancer, FAT1 is one of the most commonly mutated genes, and is considered to be an emerging cancer biomarker and a potential target for novel therapies. However, the biological functions of FAT1 and the precise downstream signaling pathways that it mediates have remained to be fully elucidated. The present review discussed the current literature on FAT1, focusing on FAT1 mutations and expression levels, and their impact on signaling pathways and mechanisms in various types of cancer, including both solid tumors and hematological malignancies, such as esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, hepatocellular carcinoma, glioma, breast cancer, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma and myeloma. The present review aimed to provide further insights and research directions for future studies on FAT1 as an oncogenic factor or tumor suppressor.
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Affiliation(s)
- Tao Wang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Junting Li
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China
| | - Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
| | - Wei Zhou
- Department of Ultrasonic Examination, Shengli Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
| | - Guang Lu
- Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
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31
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Esmaeili Z, Shavali Gilani P, Khosravani M, Motamedi M, Maleknejad S, Adabi M, Sadighara P. Nanotechnology-driven EGCG: bridging antioxidant and therapeutic roles in metabolic and cancer pathways. Nanomedicine (Lond) 2025; 20:621-636. [PMID: 39924937 PMCID: PMC11881875 DOI: 10.1080/17435889.2025.2462521] [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: 10/28/2024] [Accepted: 01/31/2025] [Indexed: 02/11/2025] Open
Abstract
Epigallocatechin-3-gallate (EGCG), the primary polyphenol in green tea, is renowned for its potent antioxidant properties. EGCG interacts with various cellular targets, inhibiting cancer cell proliferation through apoptosis and cell cycle arrest induction, while also modulating metabolic pathways. Studies have demonstrated its potential in addressing cancer development, obesity, and diabetes. Given the rising prevalence of metabolic diseases and cancers, EGCG is increasingly recognized as a promising therapeutic agent. This review provides a comprehensive overview of the latest findings on the effects of both free and nano-encapsulated EGCG on mechanisms involved in the management and prevention of hyperlipidemia, diabetes, and gastrointestinal (GI) cancers. The review highlights EGCG role in modulating key signaling pathways, enhancing bioavailability through nano-formulations, and its potential applications in clinical settings.
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Affiliation(s)
- Zahra Esmaeili
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Shavali Gilani
- Department of Environmental Health Engineering, Division of Food Safety and Hygiene, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masood Khosravani
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maral Motamedi
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shokofeh Maleknejad
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mahdi Adabi
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Food Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Sadighara
- Department of Environmental Health Engineering, Division of Food Safety and Hygiene, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Hong H, He Y, Li Y, Shen Y, Qu Y. Charting the future of esophageal cancer translation: insights from clinical trial landscape. Int J Surg 2025; 111:2731-2734. [PMID: 39878068 DOI: 10.1097/js9.0000000000002254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/11/2024] [Indexed: 01/31/2025]
Affiliation(s)
- Hujian Hong
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
- Graduate School, Dalian Medical University, Dalian, China
| | - Yijiang He
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
| | - Yan Li
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
- Graduate School, China Medical University, Shenyang, China
| | - Yongyan Shen
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
- Graduate School, China Medical University, Shenyang, China
| | - Yanli Qu
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
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Akhtar S, Al-Shammari A, Al-Huraiti M, Al-Anjery F. Age-period-cohort modeling of oesophageal carcinoma risk in a middle eastern country: 1980-2019. J Public Health (Oxf) 2025; 47:e59-e66. [PMID: 39674677 DOI: 10.1093/pubmed/fdae311] [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: 08/05/2024] [Accepted: 11/29/2024] [Indexed: 12/16/2024] Open
Abstract
BACKGROUND Understanding of the factors influencing oesophageal cancer trends is crucial. Therefore, this cross-sectional cohort study sought to disentangle the age, period and cohort effects on the trends of oesophageal cancer in Kuwait. METHODS The data on incident oesophageal carcinoma cases diagnosed between January 1, 1980, through December 31, 2019, and reference population were obtained. Age-period-cohort (APC) analysis was conducted using a loglinear Poisson regression model. RESULTS A total of 496 oesophageal carcinoma cases in 12.8 million person-years (i.e. squamous-cell carcinoma, 269, 54.23%), adenocarcinoma,147, 29.64% and unspecified cases, 80,16.13%) were diagnosed. The overall age-standardized incidence rate (per 105 person-years) of oesophageal carcinoma during the study period was 10.51 (95% CI: 6.62-14.41). The APC analysis results showed that the age and birth cohort effects were the significant determinants of declining, and subsequently steadying the oesophageal carcinoma incidence rates. CONCLUSIONS A substantial decline in oesophageal carcinoma incidence rates was recorded, which significantly varied in all three temporal dimensions. The observed birth cohort patterns suggest changing lifestyle and dietary patterns seem to be responsible for decreasing oesophageal carcinoma risk in Kuwait. Future studies may look for the component causes maintaining the endemicity of oesophageal carcinoma risk in this and similar countries in the region.
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Affiliation(s)
- Saeed Akhtar
- Department of Community Medicine and Behavioural Sciences, College of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait
| | - Ahmad Al-Shammari
- Department of Surgery, Faculty of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada
| | | | - Fouzan Al-Anjery
- Ministry of Health, Jamal Abdel Nasser Street, Sulaibkhat 13001, Kuwait
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Li H, Liang S, Cui M, Jin W, Jiang X, Lu S, Xiong J, Chen H, Wang Z, Wang G, Xu J, Li L, Wang Y, Qing H, Han Y, Leng X. A preoperative pathological staging prediction model for esophageal cancer based on CT radiomics. BMC Cancer 2025; 25:298. [PMID: 39972430 PMCID: PMC11841142 DOI: 10.1186/s12885-025-13697-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: 06/26/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Accurate and comprehensive preoperative staging is one of the most important prognostic factors for the management of esophageal cancer (EC). We aimed to develop and validate predictive models using radiomics from preoperative contrast-enhanced Computed Tomography (CT) images to assess pathological staging in EC patients. METHODS This study retrospectively included 161 patients who underwent esophagectomy at Sichuan Cancer Hospital from July 2018 to February 2023. Pathological staging outcomes encompassed overall TNM staging, T and N staging, and tumor progressions (vascular invasion and perineural invasion). Radiomics features were extracted from segmented regions of tumors. A radiomic signature (Rad-signature) for each outcome was developed using a fivefold cross-validation least absolute shrinkage and selection operator (LASSO) regression model within the training cohort and subsequently validated in the test cohort for predictive accuracy. RESULTS Out of the 851 radiomics features extracted, two were selected to formulate the Rad-signature for each staging outcome. These signatures showed a significant correlation with their respective outcomes in both the training set and the testing set. Furthermore, the Rad-signature exhibited favorable predictive performance for advanced pTNM staging, advanced pT staging, vascular invasion and perineural invasion, with AUC of 0.721 [95%CI, 0.570-0.872], 0.900 [95%CI 0.805-0.995], 0.824 [0.686-0.961], and 0.737 [0.586-0.887], respectively. However, the predictive performance of the Rad-signature for pN staging is moderate (AUC = 0.693 [0.534-0.852]), indicating needs for additional data modalities. CONCLUSIONS This study established a non-invasive preoperative radiomics model that demonstrated good predictive performance in determining the pTNM staging, pT staging, vascular invasion, and perineural invasion for EC patients. These results could inform personalized treatment strategies and improve outcomes for EC patients.
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Affiliation(s)
- Haojun Li
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Shuoming Liang
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | | | - Weiqiu Jin
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaofeng Jiang
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Simiao Lu
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Jicheng Xiong
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Hainan Chen
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Ziwei Wang
- School of Medicine, University of Electronic Science and Technology, Chengdu, China
| | - Guotai Wang
- School of Mechanical and Electrical Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiming Xu
- Yidu Cloud Technology Inc, Beijing, China
- Department of Automation, Tsinghua University, Beijing, China
| | - Linfeng Li
- Yidu Cloud Technology Inc, Beijing, China
| | - Yao Wang
- Yidu Cloud Technology Inc, Beijing, China
- Department of Automation, Tsinghua University, Beijing, China
| | - Haomiao Qing
- Department of Radiology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Yongtao Han
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuefeng Leng
- Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
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Shai SE, Kuo HJ, Lai YL, Hsieh CW. Facial metastasis of Esophageal squamous cell carcinoma. Am J Med Sci 2025:S0002-9629(25)00918-8. [PMID: 39938594 DOI: 10.1016/j.amjms.2025.02.003] [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: 06/17/2024] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 02/14/2025]
Abstract
Esophageal squamous cell carcinoma (SCC) is a highly lethal malignancy with a low survival rate, often presenting at an advanced stage. Cutaneous metastasis from esophageal SCC is exceedingly rare, affecting less than 1 % of cases, and is associated with a poor prognosis. This review particularly focuses on facial metastasis and discusses the clinical presentation, diagnostic challenges, and management of cutaneous metastases. The variability in clinical presentation often leads to misdiagnosis, delaying appropriate treatment. Histopathological examination and immunohistochemical staining are crucial for accurate diagnosis. Management involves a combination of local and systemic therapies, tailored to the patient's overall health and disease extent. This topic emphasizes the need for vigilance and thorough diagnostic workups in patients with unusual skin lesions and highlights the importance of multidisciplinary care in optimizing treatment outcomes for patients with advanced esophageal cancer.
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Affiliation(s)
- Sen-Ei Shai
- Department of Thoracic Surgery, Taichung Veterans General Hospital, Taichung, 407219, Taiwan; 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan; Department of Applied Chemistry, National Chi Nan University, Nantou, 545301, Taiwan; No. 1, Daxue Rd., Puli Township, Nantou, 545301, Taiwan; Institute of Clinical Medicine, National Yang-Ming Chiao-Tung University, Taipei, 112304, Taiwan; No. 155, Sec. 2, Linong St. Beitou Dist., Taipei, 112304, Taiwan.
| | - Hung-Ju Kuo
- Department of Thoracic Surgery, Taichung Veterans General Hospital, Taichung, 407219, Taiwan; 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan
| | - Yi-Ling Lai
- Department of Thoracic Surgery, Taichung Veterans General Hospital, Taichung, 407219, Taiwan; 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan
| | - Chi-Wei Hsieh
- School of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan; Cheng-Hsing Campus, No.1, University Road, Tainan, 701401, Taiwan
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Niu H, Wei H, Zhou X, Liu Y, Yang L, Wang Q, Luo B, Luo Q, Song F. BRD4 Induces Esophageal Squamous Cell Carcinoma Progression via the Wnt/β-catenin Pathway. Biochem Genet 2025:10.1007/s10528-025-11043-0. [PMID: 39903433 DOI: 10.1007/s10528-025-11043-0] [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: 11/07/2024] [Accepted: 01/23/2025] [Indexed: 02/06/2025]
Abstract
BRD4, part of the bromodomain and extra terminal domain (BET) protein family, plays a pivotal role in gene transcription, DNA replication, and repair via transcription regulators. Despite its established involvement in various human diseases, its function in esophageal squamous cell carcinoma (ESCC) has not been fully explored. Our research investigated the association of BRD4 in ESCC and its underlying molecular mechanisms. The findings revealed that BRD4 knockdown notably diminished the cells' proliferation, migration, invasion capabilities and induced apoptosis and cell cycle arrest. Conversely, overexpression of BRD4 can reverse these phenotypes. Pearson correlation and enrichment analyses indicated that BRD4 expression was associated with the cell cycle and Wnt/β-catenin signaling pathway. Further validation confirmed that reduced BRD4 expression downregulates Cyclin D1 and c-Myc, and suppresses epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin signaling pathway. Furthermore, rescue experiments showed that overexpressing c-Myc significantly mitigated the inhibitory impact of BRD4. Moreover, by employing single-cell transcriptome sequencing, we explored the impact of the tumor microenvironment on BRD4 overexpression in ESCC cells. These insights confirmed BRD4's potential as a therapeutic target, suggesting that modulating its expression could yield promising strategies for ESCC treatment.
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Affiliation(s)
- Haiyu Niu
- Department of Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Hanwen Wei
- Department of Cardiology, The First People's Hospital of Lanzhou, Lanzhou, 730050, China
| | - Xiaochun Zhou
- Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Yating Liu
- Department of Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Luxi Yang
- Gansu Provincial Key Laboratory of Environmental Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Qi Wang
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Benxin Luo
- Department of Internal Medicine, The People's Hospital of Zhouqu, Gannan, 746300, China
| | - Qingping Luo
- Department of Traditional Chinese Medicine, The People's Hospital of Zhouqu, Gannan, 746300, China
| | - Feixue Song
- Department of Oncology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China.
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Xiong Y, Liu YF, Yang ZH, Huang CG. Impact of miRNAs involved in the STAT3 signaling pathway on esophageal cancer (Review). Oncol Rep 2025; 53:27. [PMID: 39749694 DOI: 10.3892/or.2024.8860] [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] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Esophageal cancer (ESCA) is a common tumor noted in the digestive tract, which is highly malignant due to unclear early symptoms and poor last‑stage treatment effects; its mortality rate is relatively high. MicroRNA (miR) and signal transducer and activator of transcription 3 (STAT3) are key components of cellular signaling pathways; their interaction forms a complex and intricate information network that controls several types of biological behaviors in the cells. In the tumor cell, these signal transduction pathways are abnormally active, indicating that the STAT3 signaling pathway mediated by miRs is involved in the progression of various cancer types. The present review introduces the biological characteristics of miR and STAT3 and their relationship with ESCA. It summarizes the regulation of ESCA by the miR and STAT3 signaling pathways and analyzes the effects of these pathways on proliferation, apoptosis, invasion, metastasis and immune escape of cancer cells, as well as the impact on patient survival and prognosis. The purpose of the present review is to assess the miR/STAT3 signaling pathway in ESCA, improve the understanding of the pathogenesis of ESCA and facilitate the identification of therapeutic targets for ESCA.
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Affiliation(s)
- Ying Xiong
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yi-Fan Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Zhi-Hui Yang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Cong-Gai Huang
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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Gao W, Wang X, Shi Y, Wu G, Zhou M, Lin X. Predictable regulation of gut microbiome in immunotherapeutic efficacy of gastric cancer. Genes Immun 2025; 26:1-8. [PMID: 39533019 DOI: 10.1038/s41435-024-00306-2] [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: 05/17/2024] [Revised: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
Immunotherapy has showcased remarkable progress in the management of gastric cancer (GC), prompting the need to proactively identify and classify patients suitable for immunotherapy. Here, 30 patients were enrolled and stratified into three groups (PR, partial response; SD, stable disease; PD, progressive disease) based on efficacy assessment. 16S rRNA sequencing were performed to analyze the gut microbiome signature of patients at three timepoints. We found that immunotherapy interventions perturbed the gut microbiota of patients. Additionally, although differences at the enterotype level did not distinguish patients' immunotherapy response, we identified 6, 7, and 19 species that were significantly enriched in PR, SD, and PD, respectively. Functional analysis showed that betalain biosynthesis and indole alkaloid biosynthesis were significantly different between the responders and non-responders. Furthermore, machine learning model utilizing only bacterial biomarkers accurately predicted immunotherapy efficacy with an Area Under the Curve (AUC) of 0.941. Notably, Akkermansia muciniphila and Dorea formicigenerans played a significant role in the classification of immunotherapy efficacy. In conclusion, our study reveals that gut microbiome signatures can be utilized as effective biomarkers for predicting the immunotherapy efficacy for GC.
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Affiliation(s)
- Wei Gao
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China
| | - Xinli Wang
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China
| | - Yi Shi
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China
- Department of molecular pathology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Guangfeng Wu
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Min Zhou
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Xiaoyan Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China.
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China.
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Sasaki‐Higashimoto I, Fujishima F, Ishida H, Taniyama Y, Ozawa Y, Nakamura T, Nakaya N, Sato C, Okamoto H, Tsunokake J, Kunimitsu A, Mozumi T, Kamei T, Suzuki T. Histopathological study of the localization/distribution of Fusobacterium nucleatum in esophageal cancer. Pathol Int 2025; 75:82-91. [PMID: 39760468 PMCID: PMC11848974 DOI: 10.1111/pin.13505] [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: 08/27/2024] [Revised: 11/04/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
Fusobacterium nucleatum is implicated in esophageal cancer; however, its distribution in esophageal cancer tissues remains unknown. This study aimed to clarify the presence and distribution of F. nucleatum in esophageal cancer tissues using fluorescence in situ hybridization (FISH). Tissues collected from 70 patients with esophageal squamous cell carcinoma were examined using FISH. Corresponding normal epithelium and metastatic lymph nodes were assessed. F. nucleatum was identified more frequently in esophageal cancer tissues than in the normal epithelium. F. nucleatum also showed significant correlation with factors associated with tumor progression, such as pT factor and tumor size. As tumor progression advanced, the area occupied by F. nucleatum gradually became larger. F. nucleatum positivity was observed around the deep edge of the tumor nest (border-dense type) or identified diffusely in the tumor nest (diffuse distributed type). Furthermore, F. nucleatum was observed in metastatic lymph nodes, lesions of venous invasion, and walls of veins in normal epithelium. In conclusion, we visualized F. nucleatum using FISH and identified different distribution patterns of F. nucleatum, highlighting the spot density of its presence in tumor tissues. Recognizing this quantitative change is pivotal for establishing F. nucleatum as a reliable biomarker.
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Affiliation(s)
- Iku Sasaki‐Higashimoto
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
- Department of PathologyTohoku University HospitalSendaiJapan
| | | | - Hirotaka Ishida
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Yusuke Taniyama
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Yohei Ozawa
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Tomohiro Nakamura
- Department of Data Science, Faculty of Data ScienceKyoto Women's UniversityKyotoJapan
| | - Naoki Nakaya
- Department of Health Behavioral EpidemiologyTohoku University Graduate School of MedicineSendaiJapan
| | - Chiaki Sato
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Hiroshi Okamoto
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Junichi Tsunokake
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
- Department of PathologyTohoku University HospitalSendaiJapan
| | - Atsushi Kunimitsu
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
- Department of PathologyTohoku University HospitalSendaiJapan
| | - Takeru Mozumi
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
- Department of PathologyTohoku University HospitalSendaiJapan
| | - Takashi Kamei
- Department of SurgeryTohoku University Graduate School of MedicineSendaiJapan
| | - Takashi Suzuki
- Department of PathologyTohoku University HospitalSendaiJapan
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Mohebbi A, Mohammadzadeh S, Moradi Z, Mohammadi A, Poustchi H, Tavangar SM. Staging of esophageal cancer using PET/MRI: a systematic review with head-to-head comparison. BMC Med Imaging 2025; 25:32. [PMID: 39885424 PMCID: PMC11783729 DOI: 10.1186/s12880-025-01565-9] [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: 11/21/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025] Open
Abstract
PURPOSE To evaluate the staging performance of positron emission tomography/magnetic resonance imaging (PET/MRI) for confirmed esophageal cancer based on the TNM classification system as well as compare it to other alternative modalities (e.g., endoscopic ultrasonography (EUS), computed tomography (CT), MRI, and PET/CT) in a full head-to-head manner. METHODS Protocol was pre-registered a priori at ( http://osf.io/6qj5m/ ). We searched PubMed, Web of Science, Embase, and Cochrane Library for studies until September 10, 2024. The risk of bias was assessed using Modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Quality Assessment of Diagnostic Accuracy Studies-Comparative (QUADAS-C). The classification performance of PET/MRI in T, N, and M staging of esophageal cancer and resectability status were evaluated and compared to other relative modalities. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used for certainty evaluation. RESULTS Nine studies were included with 245 esophageal cancer patients. For T, N, and M staging, PET/MRI showed 9.1%, 2.0%, and 10.7% upstaging than the histopathological evaluation while these numbers were 19.4%, 12.4%, and 5.3% for downstaging. For direct comparison with PET/CT, PET/MRI showed 0.7% and 5.6% less downstaging and upstaging for N staging and 2.5% and 4.0% for M staging. As for predicting resectability status, pre-ADCmean and post-ADCmean were promising, unlike other parameters (i.e., ΔADCmean, pre-SUVmax, post-SUVmax, and ΔSUVmax). CONCLUSION With protocol adjustments, PET/MRI might be utilized in the future for preoperative staging of esophageal cancer. CLINICAL TRIAL NUMBER N/A.
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Affiliation(s)
- Alisa Mohebbi
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Mohammadzadeh
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Moradi
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afshin Mohammadi
- Department of Radiology, Faculty of Medicine, Urmia University of Medical Science, Urmia, Iran
| | - Hossein Poustchi
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Ramineni M, Findeis SK, Ye J, Hao Y. Paneth cell differentiation associated with neoadjuvant therapy in esophageal adenocarcinoma. Am J Clin Pathol 2025; 163:87-96. [PMID: 39110451 DOI: 10.1093/ajcp/aqae098] [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: 04/13/2024] [Accepted: 07/05/2024] [Indexed: 01/30/2025] Open
Abstract
OBJECTIVES Paneth cells and Paneth cell metaplasia are well-known in pathology as foundational components in the gastrointestinal system. When within malignant cells (Paneth cell differentiation [PCD]), however, the function and significance of these cells is less well understood. Here, we present findings from the first study focused on PCD in postneoadjuvant esophageal adenocarcinoma (EAC) resection specimens. METHODS Patients with EAC treated with neoadjuvant chemoradioation and followed by esophagectomy between 2012 and 2018 in our institution were retrospectively evaluated. A tissue microarray was constructed, and special and immunohistochemical stains were performed. RESULTS A total of 64 cases were collected, of which 8 had PCD, as highlighted by periodic acid-Schiff with diastase staining. Adenocarcinomas with PCD were more commonly seen in patients 60 to 70 years of age and typically had a poorly differentiated morphology, observationally fewer stromal mucinous changes, and less lymph node metastasis. β-catenin activation induced by neoadjuvant therapy was more frequent in the PCD-positive cases. Patients with PCD-positive disease had low programmed cell death 1 ligand 1 levels, no positive or equivocal ERBB2 (HER2) expression, and low CD8-positive T-cell infiltration; they were also mismatch repair proficient. Patients with PCD-positive disease showed a survival pattern inferior to that of patients with PCD-negative disease. CONCLUSIONS When induced by neoadjuvant therapy in EAC, PCD is associated with high β-catenin activation, less expression of targetable biomarkers, and a potentially worse clinical prognosis.
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Affiliation(s)
- Madhurya Ramineni
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, US
| | - Sarah K Findeis
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, US
| | - Jiqing Ye
- Department of Pathology and Laboratory Medicine, Rochester Regional Health, Rochester, NY, US
| | - Yansheng Hao
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, US
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Liu Y, Wang X, Zhang N, He S, Zhang J, Xu X, Song S. Utility of 131I-HLX58-Der for the Precision Treatment: Evaluation of a Preclinical Radio-Antibody-Drug-Conjugate Approach in Mouse Models. Int J Nanomedicine 2025; 20:723-739. [PMID: 39839455 PMCID: PMC11748935 DOI: 10.2147/ijn.s501689] [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: 10/20/2024] [Accepted: 01/09/2025] [Indexed: 01/23/2025] Open
Abstract
Purpose None of the antibody-drug conjugates (ADCs) targeting Claudin 18.2 (CLDN18.2) have received approval from regulatory authorities due to their limited clinical benefits. Leveraging the radiosensitizing ability of Deruxtecan (DXd) and the internal radiation therapy of 131I for tumors, we aimed to develop the first radio-antibody-drug conjugates (RADCs) for the treatment of gastric cancer. Methods The CLDN18.2-specific antibody HLX58 was conjugated with the payload DXd through a cleavable maleimide glycynglycyn-phenylalanyn-glycyn (GGFG) peptide linker. HLX58-Der was labeled with 131I to produce RADC-131I-HLX58-Der. HLX58 was labeled with 125I for imaging CLDN18.2-positive tumors, providing a reference for RADC treatment in solid tumors. The antigen-binding properties and biodistribution of the RADC were studied both in vitro and in vivo. The cytotoxic effects of the RADC were evaluated in CLDN18.2-positive tumor cell lines and xenografts. Results HLX58 was successfully conjugated with DXd using the cleavable maleimide GGFG peptide linker and labeled with 131I to produce RADC-131I-HLX58-Der. HLX58 was labeled with 125I for imaging CLDN18.2-positive tumors. Both 125I-HLX58 and 131I-HLX58-Der exhibited significant binding affinity for the CLDN18.2-positive cancer cell line. The cytotoxic effect of 131I-HLX58-Der was observed in the CLDN18.2-positive cell line, with an IC50 of 11.28 ng/mL. In terms of cytotoxicity, 131I-HLX58-Der exhibited greater activity compared to HLX58-Der. 125I-HLX58 and 131I-HLX58-Der demonstrated similar biodistribution profiles in CLDN18.2-positive tumor models, achieving 5.72 ± 0.41%ID/g (48 h) and 5.83 ± 0.41%ID/g (72 h) in the tumor tissues postinjection, respectively. The average tumor size in groups treated with 131I-HLX58-Der and HLX58-Der was reduced by factors of 12.15 and 4.80, respectively, compared to the control group. 131I-HLX58-Der demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group. Conclusion These findings validate the potential of RADCs targeting CLDN18.2 in treating CLDN18.2-expressing solid tumors.
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Affiliation(s)
- Yi Liu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
| | - Xiao Wang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang an Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, School of Public Health, Shenzhen Research Institute of Xiamen University, Xiamen University, Xiamen, 361102, People’s Republic of China
| | - Ni Zhang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
| | - Simin He
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
| | - Jianping Zhang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
| | - Xiaoping Xu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
| | - Shaoli Song
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China
- Center for Biomedical Imaging, Fudan University, Shanghai, 200032, People’s Republic of China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, 200032, People’s Republic of China
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Kennelly P, Davey MG, Griniouk D, Calpin G, Donlon NE. Evaluating the impact of enhanced recovery after surgery protocols following oesophagectomy: a systematic review and meta-analysis of randomised clinical trials. Dis Esophagus 2025; 38:doae118. [PMID: 39791389 PMCID: PMC11734668 DOI: 10.1093/dote/doae118] [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: 07/18/2024] [Revised: 11/14/2024] [Accepted: 12/18/2024] [Indexed: 01/12/2025]
Abstract
Enhanced Recovery After Surgery (ERAS) protocols are evidence-based care improvement pathways which are perceived to expedite patient recovery following surgery. Their utility in the setting of oesophagectomy remains unclear. The aim of this study was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the impact of ERAS protocols on recovery following oesophagectomy compared to standard care. A systematic review was performed in accordance with preferred reporting items for systematic reviews and meta-analyses guidelines. Meta-analysis was performed using Review Manager (Version 5.4). Six RCTs including 850 patients were included in this meta-analysis. Overall complication rate (Odds Ratio (OR): 0.35, Confidence Interval (CI): 0.21, 0.59, P < 0.0001), pulmonary complications (OR: 0.40, CI: 0.24, 0.67, P = 0.0005), post-operative length of stay (LOS) (OR -1.88, CI -2.05, -1.70, P < 0.00001) and time to post-operative flatus (OR: -5.20, CI: -9.46, -0.95, P = 0.02) favoured the ERAS group. There was no difference noted for anastomotic leak (OR: 0.55, CI: 0.24, 1.28, P = 0.17), cardiac complications (OR: 0.86, CI: 0.30, 2.46, P = 0.78), gastrointestinal complications (OR: 0.51, CI: 0.23, 1.17, P = 0.11), wound complications (OR: 0.85, CI: 0.28, 2.58, P = 0.78), mortality (OR: 1.37, CI: 0.26, 7.4, P = 0.71), and 30-day re-admission rate (OR: 1.29, CI: 0.30, 5.47, P = 0.73) between ERAS and standard care groups. ERAS implementation improved post-operative complications, LOS, and time to flatus following oesphagectomy. These results support the robust adoption of ERAS in patients indicated to undergo oesphagectomy.
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Affiliation(s)
- Patrick Kennelly
- Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | - Matthew G Davey
- Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | - Diana Griniouk
- Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | - Gavin Calpin
- Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | - Noel E Donlon
- Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
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Lai Y, Dong Y, Tian L, Li H, Ye X, Hu Y. Esophageal squamous cell carcinoma with EP300 mutations displays distinct genetic characteristics relevant to neoadjuvant chemoradiotherapy. World J Surg Oncol 2025; 23:1. [PMID: 39748249 PMCID: PMC11694467 DOI: 10.1186/s12957-024-03642-9] [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: 05/23/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND EP300 mutation is common in esophageal squamous cell carcinoma (ESCC). We aimed to analyze the influence of EP300 mutation on treatment effect and prognosis in ESCC patients underwent neoadjuvant chemoradiotherapy. METHOD Thirty ESCC patients treated with neoadjuvant chemoradiotherapy (nCRT) were enrolled in this study. After assessment of treatment response, transcriptome analyses and immunochemistry were performed for cases in well response or poor response group. RESULTS Four of thirty patients harbor EP300 mutation and have poor response to nCRT. Of the remaining 26 nonmutated patients, fifteen patients have a well response, and seven patients have a poor response to nCRT. The EP300-mutated poor response cases have significantly higher immune score than EP300 wild-type poor response cases (P = 0.002), but have no difference from EP300 wild-type well response cases (P = 0.360). Up-regulated B cell related pathways and more CD20 + B cells are in EP300-mutated poor response group, when compared with EP300 wild-type poor response group (P < 0.050). Whereas up-regulated negative regulation of cell death related pathway and higher bcl2 expression level was observed in EP300 mutated poor response group than these in EP300 wild-type well response group (P < 0.050). In prognosis, cases in EP300-mutated poor response group have worse disease-free survival (P = 0.019) and overall survival (P = 0.004) than EP300 wild-type well response group. CONCLUSION EP300 mutated cases have high immune activity in tumor microenvironment. The high anti-apoptosis activity of tumor cells may contribute to resistance to nCRT in EP300-mutated cases.
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Affiliation(s)
- Yutian Lai
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Yingxian Dong
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Long Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Hongjun Li
- West China Hospital of Medicine, Sichuan University, Chengdu, 610041, P.R. China
| | - Xinyi Ye
- Department of Endoscopy Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China
| | - Yang Hu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
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Cai Y, Ding J, Cai X, Su W, Weng G, Zheng X, Chen S, Chen L, Lin Y, Yao Q, Yang C. Constructing individualized follow-up strategies for locally advanced esophageal squamous cell carcinoma patients based on dynamic recurrence risk changes. Sci Rep 2025; 15:175. [PMID: 39747490 PMCID: PMC11695730 DOI: 10.1038/s41598-024-84099-4] [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: 07/16/2024] [Accepted: 12/19/2024] [Indexed: 01/04/2025] Open
Abstract
The aim of this study was to explore the high-risk factors for recurrence in patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing definitive chemoradiotherapy or radiotherapy (dCRT or dRT). Conditional survival (CS) was used to evaluate the dynamic survival and recurrence risk of patients after treatment, and individualized monitoring strategies were developed for patients. Logistic regression analysis was performed to determine independent recurrence risk factors. Calibration curves and receiver operating characteristic (ROC) curve were used to evaluate nomogram models. Kaplan-Meier curves were used to compare survival rates in different groups and to calculate CS rate. A total of 677 patients were included. Multivariate logistic analyses demonstrated that chemotherapy cycles, tumor length, body mass index (BMI), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were independent recurrence risk factors (p < 0.05). Subsequently, we constructed nomogram models to predict recurrence and risk stratification. Kaplan-Meier curves showed that conditional locoregional recurrence-free survival and distant metastasis-free survival of patients in different risk groups and clinical stages progressively increased with survival time, whereas local recurrence and distant metastasis annual recurrence rates decreased yearly with increasing survival time. Finally, we developed an individualized follow-up strategy based on CS at different frequencies. Individualized follow-up strategies developed on the basis of CS can better monitor the changes in patients' conditions and contribute to timely salvage treatment and rational allocation of healthcare resources.
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Affiliation(s)
- Yibin Cai
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
| | - Jianming Ding
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - XiaoJun Cai
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Weikun Su
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Guibin Weng
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Xinlong Zheng
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Shijie Chen
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lin Chen
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - YiJin Lin
- Department of Thoracic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Qiwei Yao
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
| | - Chunkang Yang
- Department of Gastrointestinal Surgical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
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Alcasid NJ, Fink D, Banks KC, Susai CJ, Barnes K, Wile R, Sun A, Patel A, Ashiku S, Velotta JB. The Impact of Diagnostic Laparoscopy on Upstaging Patients with Siewert II and III Gastroesophageal Junction (GEJ) Cancer. Ann Surg Oncol 2025; 32:258-264. [PMID: 39503948 PMCID: PMC11659370 DOI: 10.1245/s10434-024-15862-0] [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: 04/05/2024] [Accepted: 07/09/2024] [Indexed: 12/22/2024]
Abstract
BACKGROUND The efficacy of routine diagnostic laparoscopy with cytologic evaluation for gastroesophageal junction (GEJ) cancer is variable with no set guidelines. We hypothesize that findings from diagnostic laparoscopy in Siewert II and III GEJ tumors may differ, where routine diagnostic laparoscopy with washings yields low upstaging results in Siewert II compared with Siewert III tumors. PATIENTS AND METHODS We reviewed patients with Siewert II/III GEJ cancer from 2012 through 2022 within our integrated health system. Chi-squared, Fisher's exact, and two-sample Wilcoxon rank-sum tests were utilized. The outcomes measured include likelihood of upstaging, cytology positivity, times to chemotherapy and surgery, and 5-year mortality using a multivariable Cox regression model. RESULTS Of 265 patients with Siewert II diagnosis, 116 patients underwent a diagnostic laparoscopy while 149 patients did not. Median time to chemotherapy initiation and definitive surgery were increased among patients with diagnostic laparoscopy, with no difference observed in 5-year survival. For patients with Siewert II and III with a diagnostic laparoscopy, 5% of Siewert II were upstaged, compared with 17% of Siewert III (p = 0.025). Obtaining cytologic washings alone were less likely to be upstaged compared with receiving a biopsy with or without washings (5.2% vs. 17.3%, p = 0.039), and those with Siewert II were less likely than Siewert III to be upstaged after diagnostic laparoscopy (5.2% vs. 17.4%, p = 0.025). CONCLUSIONS Routine diagnostic laparoscopy yields a low upstaging rate in Siewert II GEJ adenocarcinomas (AC) while delaying treatment with no improvement on mortality. Expediting definitive surgery with selective biopsy in lieu of diagnostic laparoscopy may improve oncologic outcomes.
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Affiliation(s)
- Nathan J Alcasid
- Department of General Surgery, University of California, San Francisco-East Bay, Oakland, CA, USA.
| | - Deanna Fink
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Kian C Banks
- Department of General Surgery, University of California, San Francisco-East Bay, Oakland, CA, USA
| | - Cynthia J Susai
- Department of General Surgery, University of California, San Francisco-East Bay, Oakland, CA, USA
| | - Katherine Barnes
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Rachel Wile
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Angela Sun
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Ashish Patel
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Simon Ashiku
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Jeffrey B Velotta
- Division of Thoracic Surgery, Department of Surgery, Kaiser Permanente Northern California, Oakland, CA, USA
- Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
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Sakowitz S, Bakhtiyar SS, Mallick S, Yanagawa J, Benharash P. Travel to High-Volume Centers and Survival After Esophagectomy for Cancer. JAMA Surg 2025; 160:19-27. [PMID: 39535737 PMCID: PMC11561720 DOI: 10.1001/jamasurg.2024.5009] [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: 03/31/2024] [Accepted: 08/24/2024] [Indexed: 11/16/2024]
Abstract
Importance Ongoing efforts have encouraged the regionalization of esophageal adenocarcinoma treatment to high-volume centers (HVCs). Yet such centralization has been linked with increased patient travel burden and reduced postoperative continuity of care. Objective To determine whether traveling to undergo esophagectomy at HVCs is linked with superior overall survival compared with receiving care locally at low-volume centers (LVC). Design, Setting, and Participants This cohort study considered data for all patients diagnosed with stage I through III esophageal adenocarcinoma in the 2010-2021 National Cancer Database. Patients were stratified based on distance traveled to receive care and the annual esophagectomy volume at the treating hospital: the travel-HVC cohort included patients in the top 25th percentile of travel burden who received care at centers in the top volume quartile, and the local-LVC cohort represented those in the bottom 25th percentile of travel burden who were treated at centers in the lowest volume quartile. Data were analyzed from July 2023 to January 2024. Main Outcomes and Measures The primary end points were overall survival at 1 year and 5 years. Secondary end points included perioperative outcomes and factors linked with traveling to receive care. Results Of 17 970 patients, 2342 (13%) comprised the travel-HVC cohort, and 1969 (11%), the local-LVC cohort. The median (IQR) age was 65 (58-71) years; 3748 (87%) were male and 563 (13%) were female. After risk adjustment and with care at local LVCs as the reference, traveling to HVC was associated with superior survival at 1 year (hazard ratio for mortality [HR], 0.69; 95% CI, 0.58-0.83) and 5 years (HR, 0.80; 95% CI, 0.70-0.90). Stratifying by stage, traveling to HVCs was associated with comparable outcomes for stage I disease but reduced mortality for stage III (1-year HR, 0.72; 95% CI, 0.60-0.87; 5-year HR, 0.83; 95% CI, 0.74-0.93). Further, traveling to HVC was associated with greater lymph node harvest (β, 5.08 nodes; 95% CI, 3.78-6.37) and likelihood of margin-negative resection (adjusted odds ratio, 1.83; 95% CI, 1.29-2.60). Conclusions and Relevance Traveling to HVCs for esophagectomy was associated with improved 1-year and 5-year survival compared with receiving care locally at LVCs, particularly among patients with locoregionally advanced disease. Future studies are needed to ascertain barriers to care and develop novel targeted pathways to ensure equitable access to high-volume facilities and high-quality oncologic care.
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Affiliation(s)
- Sara Sakowitz
- Cardiovascular Outcomes Research Laboratories (CORELAB), University of California, Los Angeles
| | - Syed Shahyan Bakhtiyar
- Cardiovascular Outcomes Research Laboratories (CORELAB), University of California, Los Angeles
- Department of Surgery, University of Colorado, Aurora
| | - Saad Mallick
- Cardiovascular Outcomes Research Laboratories (CORELAB), University of California, Los Angeles
- Center for Advanced Surgical & Interventional Technology, Department of Surgery, University of California, Los Angeles
| | - Jane Yanagawa
- Division of Thoracic Surgery, Department of Surgery, University of California, Los Angeles
| | - Peyman Benharash
- Cardiovascular Outcomes Research Laboratories (CORELAB), University of California, Los Angeles
- Center for Advanced Surgical & Interventional Technology, Department of Surgery, University of California, Los Angeles
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Saini A, Saini V, Deswal G, Chopra B, Grewal AS, Dhingra AK. Harnessing Therapeutic Potential of Allicin Against Cancer: An Exploratory Review. Anticancer Agents Med Chem 2025; 25:589-602. [PMID: 39851103 DOI: 10.2174/0118715206343978241223080625] [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: 07/12/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 01/26/2025]
Abstract
BACKGROUND The biological name of garlic is Allium sativum L., a familiar spice with various health benefits. These benefits are mainly attributable to the compound diversity of garlic, which includes saponins, polysaccharides, organic sulfides, and phenolic compounds. Allicin exhibits therapeutic activity such as antibacterial, anticancer, anti-inflammatory, immunomodulatory, anti-diabetic, and cardiovascular protection. This present study explores the anticancer potential of allicin, including cell line studies that examine its effects on various cancer types by analyzing the growth inhibition of cancer cells at different allicin concentrations. AIM This study aims to present a concise overview of allicin, update patent statistics, and provide detailed insights into its wide range of therapeutic benefits, with a particular emphasis on its anticancer properties. METHODS A literature review has been conducted using reliable sources, including ClinicalTrials.gov, ScienceDirect, PubMed, Scopus, and other reputable foundations, to assess the true potential of allicin in cancer therapeutics. RESULTS Allicin, a naturally occurring compound in garlic, represents a promising treatment approach for cancer due to its potent anticancer properties. Cell line studies have shown that various concentrations of allicin significantly inhibit cancer cell growth, underscoring its effectiveness against cancer types such as breast, pancreatic, liver, renal, osteosarcoma, gastric, colorectal, and stomach cancers. By effectively targeting cancer cells, allicin stands out as a potential therapeutic agent. CONCLUSION The primary goal of the review is to highlight the anticancer potential of allicin, along with an overview of clinical and patent studies.
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Affiliation(s)
- Anmol Saini
- Global Research Institute of Pharmacy, Radaur, Yamuna Nagar, Haryana, 135133, India
| | - Vishakha Saini
- Global Research Institute of Pharmacy, Radaur, Yamuna Nagar, Haryana, 135133, India
| | - Geeta Deswal
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, 135001, India
| | - Bhawna Chopra
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, 135001, India
| | - Ajmer Singh Grewal
- Guru Gobind Singh College of Pharmacy, Yamuna Nagar, Haryana, 135001, India
| | - Ashwani K Dhingra
- Global Research Institute of Pharmacy, Radaur, Yamuna Nagar, Haryana, 135133, India
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Wang J, Zhu Y, Li Q, Wang L, Bian H, Lu X, Ye Z. Spectral CT-based nomogram for evaluation of neoadjuvant chemotherapy response in esophageal squamous cell carcinoma. Eur Radiol 2024:10.1007/s00330-024-11294-2. [PMID: 39729110 DOI: 10.1007/s00330-024-11294-2] [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: 07/20/2024] [Revised: 10/15/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024]
Abstract
OBJECTIVES To establish a spectral CT-based nomogram for predicting the response to neoadjuvant chemotherapy (NAC) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS This retrospective study included 172 patients with ESCC who underwent spectral CT scans before NAC followed by resection. Based on postoperative tumor regression grades (TRG), 34% (58) of patients were responsive (TRG1) and 66% (114) were non-responsive (TRG2-3). The data was divided into a primary set of 120 and a validation set of 52, maintaining a 7:3 random ratio. Measurements included iodine concentration (IC), normalized iodine concentration (nIC), CT40kev, CT70kev, spectral attenuation curve slope (λHU), and effective atomic number (Zeff) during non-contrast and venous phases (VP). Clinicopathologic characteristics were collected. Univariable and multivariable logistic regressions identified independent predictors of NAC response. The model was visualized using nomograms, and its efficacy was assessed via receiver operating characteristic (ROC) curves. RESULTS Multivariable logistic regression analysis identified the neutrophil-to-lymphocyte ratio (NLR), clinical stage, ZeffVP, and nICVP as independent predictors of NAC response. The nomogram incorporating all four independent predictors, outperformed spectral CT and the clinical model with the highest AUCs of 0.825 (95% CI: 0.746-0.895) for the primary set and 0.794 (95% CI: 0.635-0.918) for the validation set (DeLong test: all p < 0.05). CONCLUSIONS The spectral CT and clinical models were useful in predicting NAC response in ESCC patients. Combining spectral CT imaging parameters and clinicopathologic characteristics in a nomogram improved predictive accuracy. KEY POINTS Question Developing a non-invasive, practical tool to predict ESCC's response to chemotherapy is crucial and has not yet been done. Findings This nomogram, incorporating clinicopathologic characteristics and spectral CT-derived parameters, predicted NAC response in ESCC patients. Clinical relevance This spectral CT-based nomogram is a non-invasive and easily obtainable tool for accurately predicting ESCC response to NAC, aiding clinicians in personalized treatment planning.
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Affiliation(s)
- Jing Wang
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Yueqiang Zhu
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Qian Li
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Lining Wang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Haiman Bian
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xiaomei Lu
- CT Clinical Science CT, Philips Healthcare, Beijing, China
| | - Zhaoxiang Ye
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
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Bao Y, Wang X, Zeng B, Shi Y, Huang Y, Huang Y, Shang S, Shan L, Ma L. Research Progress of Liquid Biopsy Based on DNA Methylation in Tumor Diagnosis and Treatment. Biomolecules 2024; 14:1634. [PMID: 39766341 PMCID: PMC11727523 DOI: 10.3390/biom14121634] [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: 10/23/2024] [Revised: 11/29/2024] [Accepted: 12/16/2024] [Indexed: 01/15/2025] Open
Abstract
Liquid biopsy has been gradually applied to the clinical diagnosis and treatment of tumors because of its non-invasive and real-time reflection of the tumor status, as well as the convenience of sample collection, which allows the detection of primary or metastatic malignant tumors and reflects the heterogeneity of the tumors. DNA methylation, which is a type of epigenetic modification, is essential in the progression of tumors. This review introduces the common DNA methylation analysis methods and discusses their advantages and disadvantages, focusing on the new progress of DNA methylation-based liquid biopsy in tumor diagnosis and treatment.
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Affiliation(s)
- Yunxia Bao
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xianzhao Wang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Bingjie Zeng
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yichun Shi
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yiman Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yiwen Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Shuang Shang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Liang Shan
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lifang Ma
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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