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He JJ, Xiong WL, Sun WQ, Pan QY, Xie LT, Jiang TA. Advances and current research status of early diagnosis for gallbladder cancer. Hepatobiliary Pancreat Dis Int 2025; 24:239-251. [PMID: 39393997 DOI: 10.1016/j.hbpd.2024.09.011] [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: 06/04/2024] [Accepted: 09/26/2024] [Indexed: 10/13/2024]
Abstract
Gallbladder cancer (GBC) is the most common malignant tumor in the biliary system, characterized by high malignancy, aggressiveness, and poor prognosis. Early diagnosis holds paramount importance in ameliorating therapeutic outcomes. Presently, the clinical diagnosis of GBC primarily relies on clinical-radiological-pathological approach. However, there remains a potential for missed diagnosis and misdiagnose in the realm of clinical practice. We firstly analyzed the blood-based biomarkers, such as carcinoembryonic antigen and carbohydrate antigen 19-9. Subsequently, we evaluated the diagnostic performance of various imaging modalities, including ultrasound (US), endoscopic ultrasound (EUS), computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT) and pathological examination, emphasizing their strengths and limitations in detecting early-stage GBC. Furthermore, we explored the potential of emerging technologies, particularly artificial intelligence (AI) and liquid biopsy, to revolutionize GBC diagnosis. AI algorithms have demonstrated improved image analysis capabilities, while liquid biopsy offers the promise of non-invasive and real-time monitoring. However, the translation of these advancements into clinical practice necessitates further validation and standardization. The review highlighted the advantages and limitations of current diagnostic approaches and underscored the need for innovative strategies to enhance diagnostic accuracy of GBC. In addition, we emphasized the importance of multidisciplinary collaboration to improve early diagnosis of GBC and ultimately patient outcomes. This review endeavoured to impart fresh perspectives and insights into the early diagnosis of GBC.
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Affiliation(s)
- Jia-Jia He
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Ultrasound Medicine, Beilun District People's Hospital, Ningbo 315800, China
| | - Wei-Lv Xiong
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Ultrasound Medicine, Huzhou Central Hospital, Huzhou 313000, China
| | - Wei-Qi Sun
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Ultrasound Medicine, The Second Affiliated Hospital, Jiaxing University, Jiaxing 314000, China
| | - Qun-Yan Pan
- Department of Ultrasound Medicine, Beilun District People's Hospital, Ningbo 315800, China
| | - Li-Ting Xie
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Tian-An Jiang
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Xu S, Xu M. Advances in diagnosis and treatment of gallbladder cancer: Current status and future directions. World J Gastrointest Oncol 2025; 17:104957. [DOI: 10.4251/wjgo.v17.i5.104957] [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: 01/06/2025] [Revised: 03/07/2025] [Accepted: 03/18/2025] [Indexed: 05/15/2025] Open
Abstract
Gallbladder cancer (GBC) is a rare but aggressive cancer that often presents subtle early symptoms, leading to late-stage diagnosis. In recent years, significant advancements have been made in early detection and treatment of GBC. These improvements are driven by a better understanding of the risk factors for this malignancy and the use of new diagnostic technologies. This review systematically examines the risk factors associated with GBC, and advancements in diagnostic techniques and treatment strategies, with an aim to enhance the early diagnosis and effective management of GBC to provide a valuable reference for clinical practice.
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Affiliation(s)
- Song Xu
- Department of Hepatobiliary Surgery, Shangyu People’s Hospital of Shaoxing, Shaoxing 312300, Zhejiang Province, China
| | - Ming Xu
- Department of Hepatic-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
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3
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Dong M, Chen J, Lu N, Wang S, Wei W, Wang Z, Wang J, Zhang J, Han X, Wang F, Ou Q, Bao H, Ma X, Shan B, Pan Y. Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis. Breast Cancer Res 2025; 27:64. [PMID: 40312292 PMCID: PMC12044986 DOI: 10.1186/s13058-025-02026-5] [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: 03/03/2025] [Accepted: 04/16/2025] [Indexed: 05/03/2025] Open
Abstract
INTRODUCTION Neoadjuvant chemotherapy (NAC) is a standard treatment for breast cancer (BC) to shrink tumors and facilitate surgery. However, the molecular underpinnings of response to NAC and prognosis have not been well characterized. METHODS We enrolled 73 stage II/III BC patients who received NAC followed by surgery. Tumor tissue samples were available from 36 patients at baseline and 38 at the time of surgery. Plasma circulating tumor DNA (ctDNA) was collected at three time points: before NAC (n = 63), during NAC (n = 42), and after NAC (n = 40). Comprehensive genomic, transcriptomic, and ctDNA analyses were performed to identify biomarkers associated with pathological complete response (pCR) and survival outcomes. RESULTS Nine baseline mutations, including DNHD1 and PLEC, along with HIPPO pathway alterations, were associated with pCR. Responsive tumors exhibited immune activation and downregulated PI3K-Akt and AGE-RAGE pathways, while non-pCR tumors showed reduced cytokine and immune receptor activity. Undetectable ctDNA during and after NAC was predictive of treatment efficacy and correlated with improved survival. Baseline mutations in USH2A were associated with shorter disease-free survival (hazard ratio: 11.9; 95% confidence interval: 2.8-50.8; P < 0.001), with a consistent trend observed for overall survival. Elevated NHSL1 expression in baseline tumors indicated an initial treatment response but was later associated with tumor relapse and poor overall survival (P = 0.026 and P = 0.023, respectively), findings that were validated in an independent clinical cohort (N = 30) through immunohistochemistry staining. CONCLUSION Our comprehensive multi-omics analysis identified promising biomarkers predictive of treatment response and survival in BC patients receiving NAC followed by surgery. These findings underscore the importance of early tumor assessment for improved patient stratification and prognostication.
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Affiliation(s)
- Menghao Dong
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Jian Chen
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Nannan Lu
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Song Wang
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, China
| | - Wenhui Wei
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Ziming Wang
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Jinnan Wang
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Jinguo Zhang
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Xinghua Han
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China
| | - Fufeng Wang
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, China
| | - Qiuxiang Ou
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, China
| | - Hua Bao
- Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, China
| | - Xiaopeng Ma
- Department of Breast Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China.
| | - Benjie Shan
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China.
| | - Yueyin Pan
- Department of Clinical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, No. 17 Lujiang Road, Luyang District, Hefei, Anhui, 230001, China.
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Shen TH, Yu X, Zhou C, Liu Y, Li QY, Li W, Jiang TH, Zhu YQ, Liu Y. Review of the mechanisms of the biliary-enteric axis in the development of cholangiocarcinoma. World J Clin Oncol 2025; 16:102374. [PMID: 40290694 PMCID: PMC12019280 DOI: 10.5306/wjco.v16.i4.102374] [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: 10/15/2024] [Revised: 01/07/2025] [Accepted: 02/13/2025] [Indexed: 03/26/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a particularly aggressive and challenging type of cancer, known for its poor prognosis, which is worsened by the complex interplay of various biological and environmental factors that contribute to its development. Recently, researchers have increasingly focused on the significant role of the biliary-enteric communication of liver-gut axis in the pathogenesis of CCA, highlighting a complex relationship that has not been thoroughly explored before. This review aims to summarize the key concepts related to the biliary-enteric communication of liver-gut axis and investigate its potential mechanisms that may lead to the onset and progression of CCA, a disease that presents substantial treatment challenges. Important areas of focus will include the microbiome's profound influence, which interacts with host physiology in ways that may worsen cancer development; changes in bile acid metabolism that can create toxic environments favorable for tumor growth; the regulation of inflammatory processes that may either promote or inhibit tumor progression; the immune system's involvement, which is crucial in the body's response to cancer; and the complex interactions within metabolic pathways that can affect cellular behavior and tumor dynamics. By integrating recent research findings from various studies, we aim to explore the multifaceted roles of the biliary-enteric communication of liver-gut axis in CCA, providing new insights and perspectives for future research while identifying promising therapeutic targets that could lead to innovative treatment strategies aimed at improving patient outcomes in this challenging disease.
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Affiliation(s)
- Tian-Hao Shen
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Xue Yu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Cheng Zhou
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yu Liu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Qiu-Ying Li
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Wei Li
- Department of Hepatological Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ting-Hui Jiang
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yong-Qiang Zhu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Yan Liu
- Department of Interventional Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
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Cui S, Zheng H, Xu Y, Wu Q, Liu W, Cai Y, Fan L, Tian Y, Qian H, Ding Y, Zhang X, Zhang J, Wu X, Wang R, Li X, Chen X. Plasma proteomic biomarkers predict therapeutic responses in advanced biliary tract cancer patients receiving Camrelizumab plus the GEMOX treatment. NPJ Precis Oncol 2025; 9:102. [PMID: 40195413 PMCID: PMC11977001 DOI: 10.1038/s41698-025-00879-9] [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: 10/26/2024] [Accepted: 03/13/2025] [Indexed: 04/09/2025] Open
Abstract
Biliary tract cancer (BTC) has greatly influenced patient survival for years. Nowadays, immunotherapy represents a promising breakthrough and proteomics is one of powerful technologies in biomarker research. We collected plasma and tissue samples from 37 patients with advanced BTC and 92 proteins were analyzed by proximity extension assay (PEA). Through linear mixed effect models, compared to partial response (PR) group, 8 proteins, IL7, ANGPT2, IL15, HO-1, CXCL1, CXCL5, IL33, and VEGFA, exhibited significantly higher expression in stable disease and progressive disease (SD_PD) group in response-effect analysis. It was also revealed that a subset of proteins increased over time, including PDCD1, TNFRSF4, DCN, CRTAM, VEGFR-2 and ADA in PR group and PDCD1, IL10, ADA, CD28, and PTN in SD_PD group. In interaction-effect analysis, HO-1, ANGPT2, IL15 were three significant differentially expressed proteins (DEPs). Receiver operating characteristic (ROC) analysis further demonstrated that HO-1, ANGPT2, IL15 showed high accuracy in patients with immune checkpoint blockade (ICB) treatment plus chemotherapy (AUC = 0.74). In addition, based on the obtained plasma and tissue samples, two nomogram models were constructed for predicting the prognosis of BTC by genome combined with proteomics. Collectively meaningful proteomic biomarkers are beneficial to evaluate the efficacy of immunotherapy, and these discovered biomarkers may be included in the scope of treatments' evaluation and improvement in future study.
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Affiliation(s)
- Shiyun Cui
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, P. R. China
- Department of oncology, Chongqing Hospital of Jiangsu Province Hospital (The People's Hospital of Qijiang District), Chongqing, 401420, China
| | - Hejian Zheng
- Department of oncology, Chongqing Hospital of Jiangsu Province Hospital (The People's Hospital of Qijiang District), Chongqing, 401420, China
| | - Yiyang Xu
- Nanjing Medical University, Nanjing, 210029, China
| | - Qiuyu Wu
- Nanjing Medical University, Nanjing, 210029, China
| | - Weici Liu
- Nanjing Medical University, Nanjing, 210029, China
| | - Yucheng Cai
- Nanjing Medical University, Nanjing, 210029, China
| | - Lei Fan
- Department of General Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Yitong Tian
- Nanjing Medical University, Nanjing, 210029, China
| | - Hao Qian
- Nanjing Medical University, Nanjing, 210029, China
| | - Yuting Ding
- Nanjing Medical University, Nanjing, 210029, China
| | - Xinyi Zhang
- Nanjing Medical University, Nanjing, 210029, China
| | | | - Xiaofeng Wu
- Hepatobiliar k77y Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Rong Wang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, P. R. China.
| | - Xiangcheng Li
- Hepatobiliar k77y Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Xiaofeng Chen
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, P. R. China.
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, P. R. China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
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Chen R, Ma C, Qian H, Xie X, Zhang Y, Lu D, Hu S, Zhang M, Liu F, Zou Y, Gao Q, Zhou H, Liu H, Lin M, Ge G, Gao D. Mutant KRAS and CK2 Cooperatively Stimulate SLC16A3 Activity to Drive Intrahepatic Cholangiocarcinoma Progression. Cancer Res 2025; 85:1253-1269. [PMID: 39854318 DOI: 10.1158/0008-5472.can-24-2097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/14/2024] [Accepted: 01/16/2025] [Indexed: 01/26/2025]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy affecting the liver and biliary system. Enhanced understanding of the pathogenic mechanisms underlying iCCA tumorigenesis and the discovery of appropriate therapeutic targets are imperative to improve patient outcomes. In this study, we investigated the functions and regulations of solute carrier family 16 member 3 (SLC16A3), which has been reported to be a biomarker of poor prognosis in iCCA. High SLC16A3 expression was enriched in KRAS viral oncogene homolog-mutated iCCA tumors, and mutant KRAS elevated SLC16A3 expression via the PI3K-AKT-mTORC1-HIF1α pathway. SLC16A3 not only enhanced glycolysis but also induced epigenetic reprogramming to regulate iCCA progression. Phosphorylation of SLC16A3 at S436 was vital for its oncogenic function and was linked to iCCA progression. Casein kinase 2 (CK2) directly phosphorylated SLC16A3 at S436, and CK2 inhibition with CX-4945 (silmitasertib) reduced the growth of KRAS-mutated iCCA tumor xenografts and patient-derived organoids. Together, this study provides valuable insights into the diverse functions of SLC16A3 in iCCA and comprehensively elucidates the upstream regulatory mechanisms, providing potential therapeutic strategies for patients with iCCA with KRAS mutations. Significance: Characterization of the oncogenic function and regulators of SLC16A3 in intrahepatic cholangiocarcinogenesis revealed the potential of CK2 inhibitors as a promising treatment for KRAS-mutated tumors.
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Affiliation(s)
- Ran Chen
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Cuihong Ma
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Haoran Qian
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xinyu Xie
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yuxue Zhang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dayun Lu
- Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shunjie Hu
- Department of Hepatobiliary Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mao Zhang
- Department of Hepatobiliary Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fen Liu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yunhao Zou
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Gao
- Department of Hepatobiliary Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Hu Zhou
- University of Chinese Academy of Sciences, Beijing, China
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Hailong Liu
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Moubin Lin
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Gaoxiang Ge
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Daming Gao
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
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Yasui Y, Kimura K, Iseda N, Nobuto Y, Yano H, Kajiwara Y, Watanabe T, Cao F, Amano M, Tanaka T, Ochi H, Azemoto N, Minami K, Minagawa R, Yokota T, Nishizaki T. Hilar Cholangiocarcinoma with Para-Aortic Lymph Node Metastasis Treated with Chemoimmunotherapy and Conversion Surgery: A Case Report. Surg Case Rep 2025; 11:25-0023. [PMID: 40115219 PMCID: PMC11925595 DOI: 10.70352/scrj.cr.25-0023] [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: 01/28/2025] [Accepted: 03/02/2025] [Indexed: 03/23/2025] Open
Abstract
INTRODUCTION Cholangiocarcinoma (CC) has a poor prognosis and few treatment options. Conversion surgery for unresectable CC has been frequently reported; however, there are almost no reports of conversion surgery after durvalumab plus gemcitabine and cisplatin therapy. In this study, we report the case of a patient with unresectable hilar CC who received durvalumab plus gemcitabine and cisplatin therapy and achieved a pathological complete response after conversion surgery. CASE PRESENTATION A 70-year-old man was diagnosed with hilar CC (cT3N1M0, Stage III C) based on biopsy of the common bile duct stenosis and computed tomography (CT) and magnetic resonance cholangiopancreatography scans. Initially, a right lobe hepatectomy and subtotal stomach-preserving pancreatoduodenectomy were planned. However, there were concerns about an insufficient functional remnant liver volume. Trans-ileocolic portal embolization of the right portal vein branch was performed. On a preoperative CT scan 1 month later for liver volumetry, swelling of the para-aortic lymph nodes was observed, which was judged as distant metastasis, and radical resection could not be performed. After 8 courses of durvalumab plus gemcitabine and cisplatin therapy, vanishing fluorodeoxyglucose accumulation in the para-aortic lymph nodes was observed on positron emission tomography-CT. The possibility of resection was reevaluated, and a right lobe hepatectomy and extrahepatic biliary reconstruction were performed as conversion surgeries. Histological examination confirmed the absence of residual tumors or lymph node metastases. Ten months after surgery, the patient was free of recurrence. CONCLUSIONS Chemoimmunotherapy with durvalumab as a first-line treatment for unresectable CC has shown promising results. Immunotherapy with durvalumab, followed by conversion surgery, may improve the prognosis of patients with unresectable CC.
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Affiliation(s)
- Yuma Yasui
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Koichi Kimura
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Norifumi Iseda
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Yoshinari Nobuto
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Hiroko Yano
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Yuichiro Kajiwara
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Takuro Watanabe
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Fang Cao
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Michiko Amano
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Takaaki Tanaka
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Hironori Ochi
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Nobuaki Azemoto
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Kazuhito Minami
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Ryosuke Minagawa
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Tomoyuki Yokota
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Takashi Nishizaki
- Department of Surgery, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
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Wang KX, Yang XD, Guo F, Sun H, Fang YY, Jiang NY, Chen XF. Comprehensive clinical and genetic characterization of hyperprogressive biliary tract cancer during PD-1 blockade monotherapy: case report and literature review. BMC Med Genomics 2025; 18:52. [PMID: 40087618 PMCID: PMC11909846 DOI: 10.1186/s12920-025-02097-5] [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: 02/26/2024] [Accepted: 01/29/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Some genetically characterized patients show the rapid disease progression during immune checkpoint inhibitors (ICIs) monotherapy, a phenomenon known as hyperprogressive disease (HPD). CASE PRESENTATION Herein we report a relevant case of biliary tract cancer (BTC) that initially responded to gemcitabine plus oxaliplatin (GEMOX) and PD-1 blockade but subsequently developed HPD in the process of PD-1 blockade maintenance therapy, leading to death within two weeks. Genomic analysis revealed mutations in CDKN2A, PIK3CA, KRAS and EPHA2 in both baseline and hyperprogressive plasma and tumor samples. Notably, higher KRAS mutation abundance was observed in plasma and ascites after disease progression. CONCLUSIONS These findings suggest a potential association between these negative genes especially KRAS mutation and HPD. Therefore, administration of PD-1 blockade monotherapy in this subgroup of patients harboring KRAS mutation should be performed with caution. Further studies are warranted to confirm these results and explore the correlation between genomic mutations and HPD.
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Affiliation(s)
- Kang-Xin Wang
- Department of Oncology, The Affiliated Nanjing Pukou People's Hospital of Jiangsu Health Vocational College, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China
| | - Xu-Dong Yang
- Department of General Surgery, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China
| | - Fen Guo
- Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215001, China
| | - Hui Sun
- Department of Oncology, The Affiliated Nanjing Pukou People's Hospital of Jiangsu Health Vocational College, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China
| | - Yue-Yu Fang
- Department of Oncology, The Affiliated Nanjing Pukou People's Hospital of Jiangsu Health Vocational College, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China
| | - Nan-Yuan Jiang
- Department of Oncology, The Affiliated Nanjing Pukou People's Hospital of Jiangsu Health Vocational College, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China
| | - Xiao-Feng Chen
- Department of Oncology, The Affiliated Nanjing Pukou People's Hospital of Jiangsu Health Vocational College, Nanjing Pukou People's Hospital, Liangjiang Hospital Southeast University, Nanjing, 211800, China.
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, 210029, China.
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9
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Liu QQ, Yan J, Ye YF, Yang CN, Chen ZJ, Lin HM, Zhang ZT, Zhang R. Efficacy and conversion outcome of chemotherapy combined with PD-1 inhibitor for patients with unresectable or recurrent gallbladder carcinoma: a real-world exploratory study. World J Surg Oncol 2025; 23:69. [PMID: 40022061 PMCID: PMC11869664 DOI: 10.1186/s12957-025-03703-7] [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: 09/03/2024] [Accepted: 02/03/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND Gallbladder carcinoma (GBC) is an extremely aggressive tumor of the biliary tract with a bleak prognosis, and the evidence supporting the benefit of available systemic therapy for advanced GBC is scarce. Herein, this study intended to investigate the real-world outcome of chemotherapy combined with programmed death-1 (PD-1) inhibitor for the management of unresectable or recurrent GBC. METHODS From January 2018 to December 2023, consecutive patients who were treated with systematic treatment, including chemotherapy or the combination of chemotherapy plus PD-1 inhibitor, for unresectable or recurrent GBC were retrospectively identified. Clinical data regarding baseline characteristics, therapeutic response, adverse events (AEs), and oncological outcomes were collected. RESULTS The eligible patients were allocated to combination therapy arm (n = 46) and mono-chemotherapy arm (n = 19). After propensity score matching (PSM), 16 patients were allocated in each arm. The overall survival (OS) and progression-free survival (PFS) of combination therapy were marginally superior to mono-chemotherapy both before and after PSM. The combination therapy exhibited advantage over mono-chemotherapy in regards to partial response (PR) (before PSM: P = 0.009; after PSM: P = 0.037) and objective response rate (ORR) (before PSM: P = 0.006; after PSM: P = 0.015). In combined therapy cohort, 1 patient achieve a complete response, and 13 patients were assessed as appropriate for surgical excision, among which 1 patient refused further surgical intervention. CONCLUSIONS In patients with unresectable or recurrent GBC, the combination of chemotherapy and PD-1 inhibitor as first-line therapy exhibited prolonged OS and PFS, and increased PR and ORR over those receiving chemotherapy alone, with an acceptable toxicity profile. The combination therapy may be a potential conversion therapy in unresectable GBC patients.
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Affiliation(s)
- Qin-Qin Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Guangdong, China
| | - Jian Yan
- Department of Hepatobiliary surgery, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Yan-Fang Ye
- Clinical Research Design Division, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Cai-Ni Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Zhi-Jun Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Hao-Ming Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | | | - Rui Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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10
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Bousou TE, Sarantis P, Anastasiou IA, Trifylli EM, Liapopoulos D, Korakaki D, Koustas E, Katsimpoulas M, Karamouzis MV. Biomarkers for the Evaluation of Immunotherapy in Patients with Cholangiocarcinoma. Cancers (Basel) 2025; 17:555. [PMID: 39941920 PMCID: PMC11817672 DOI: 10.3390/cancers17030555] [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: 12/22/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Cholangiocarcinoma is a rare primary liver cancer with poor prognosis, due to the advanced stage at the time of diagnosis and limited therapeutic options, with poor response. Chemotherapy remains the standard first-line treatment, but the advent of immunotherapy has recently induced promising results. Given the fact that diagnosis frequency is increasing nowadays and the survival rate remains very low, it is crucial to recognize patients who are suitable for immunotherapy and will have the best response. Different types of biomarkers, such as interleukins, exosomes, mi-RNA, ctDNA, and gene mutations, have been studied for their feasibility, not only for the early diagnosis of biliary tract cancer but also for the determination of responsiveness in treatment. Less frequently, these studies focus on finding and observing biomarkers in patients who receive immunotherapy. This review aims to summarize current knowledge of existing/promising biomarkers in patients with unresectable or metastatic cholangiocarcinoma, treated with immunotherapy as monotherapy, or combined with chemotherapy.
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Affiliation(s)
- Thaleia-Eleftheria Bousou
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Panagiotis Sarantis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Ioanna A. Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece;
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Agiou Thoma 17, 115 27 Athens, Greece
| | - Eleni-Myrto Trifylli
- GI-Liver Unit, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 115 27 Athens, Greece;
| | - Dimitris Liapopoulos
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
| | - Dimitra Korakaki
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Evangelos Koustas
- Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece;
| | - Michalis Katsimpoulas
- Experimental Surgery Unit, Center of Clinical, Experimental Surgery and Translational Research, Βiοmedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou, 115 27 Athens, Greece;
| | - Michalis V. Karamouzis
- University Pathology Clinic, General and Oncology Hospital “Agioi Anargyroi”, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece; (T.-E.B.); (D.L.); (D.K.)
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11
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Xu R, Lin P, Zheng J, Lin Y, Mai Z, Lu Y, Chen X, Zhou Z, Cui L, Zhao X. Orchestrating cancer therapy: Recent advances in nanoplatforms harmonize immunotherapy with multifaceted treatments. Mater Today Bio 2025; 30:101386. [PMID: 39742149 PMCID: PMC11683241 DOI: 10.1016/j.mtbio.2024.101386] [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: 09/15/2024] [Revised: 11/17/2024] [Accepted: 12/05/2024] [Indexed: 01/03/2025] Open
Abstract
Advancements in cancer therapy have increasingly focused on leveraging the synergistic effects of combining immunotherapy with other treatment modalities, facilitated by the use of innovative nanoplatforms. These strategies aim to augment the efficacy of standalone treatments while addressing their inherent limitations. Nanoplatforms enable precise delivery and controlled release of therapeutic agents, which enhances treatment specificity and reduces systemic toxicity. This review highlights the critical role of nanomaterials in enhancing immunotherapy when combined with chemotherapy, radiotherapy, photodynamic therapy, photothermal therapy, and sonodynamic therapy. Additionally, it addresses current challenges, including limited in vivo studies, difficulties in standardizing and scaling production, complexities of combination therapies, lack of comparative analyses, and the need for personalized treatments. Future directions involve refining nanoplatform engineering for improved targeting and minimizing adverse effects, alongside large animal studies to establish the long-term efficacy and safety of these combined therapeutic strategies. These efforts aim to translate laboratory successes into clinically viable treatments, significantly improving therapeutic outcomes and advancing the field of oncology.
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Affiliation(s)
- Rongwei Xu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Pei Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Jiarong Zheng
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yunfan Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Zizhao Mai
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Ye Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Xu Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Zihao Zhou
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Li Cui
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
- School of Dentistry, University of California, Los Angeles, Los Angeles, 90095, CA, USA
| | - Xinyuan Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, Guangdong, China
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12
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Ricci AD, Rizzo A, Schirizzi A, D’Alessandro R, Frega G, Brandi G, Shahini E, Cozzolongo R, Lotesoriere C, Giannelli G. Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Regulatory Mechanisms, Functions, and Therapeutic Implications. Cancers (Basel) 2024; 16:3542. [PMID: 39456636 PMCID: PMC11505966 DOI: 10.3390/cancers16203542] [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: 09/18/2024] [Revised: 10/06/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.
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Affiliation(s)
- Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Alessandro Rizzo
- S.S.D. C.O.r.O. Bed Management Presa in Carico, TDM, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Giorgio Frega
- Osteoncology, Soft Tissue and Bone Sarcomas, Innovative Therapy Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
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13
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Wang S, Chao J, Wang H, Li S, Wang Y, Zhu C, Zhang N, Piao M, Yang X, Liu K, Xun Z, Sang X, Yang X, Duan W, Zhao H. Effectiveness, safety, and biomarker analysis of lenvatinib plus toripalimab as chemo-free therapy in advanced intrahepatic cholangiocarcinoma: a real-world study. Cancer Immunol Immunother 2024; 73:249. [PMID: 39358645 PMCID: PMC11447168 DOI: 10.1007/s00262-024-03841-z] [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: 08/04/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC. METHODS This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted. RESULTS A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016). CONCLUSION Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers.
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Affiliation(s)
- Shanshan Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Jiashuo Chao
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Hao Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Shuofeng Li
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Yunchao Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
- Organ Transplantation Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chengpei Zhu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
- Department of General Surgery Center, Beijing Youan Hospital, Clinical Center for Liver Cancer, Capital Medical University, Beijing, China
| | - Nan Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Mingjian Piao
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Xu Yang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Kai Liu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Ziyu Xun
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Xinting Sang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Xiaobo Yang
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China.
| | - Weidong Duan
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing, China.
| | - Haitao Zhao
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China.
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14
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Lu Y, Jin Y, Liu F, Wang Z, Zhou W, Zhang Y, Bai B, Wang Y, Wang Z, Nie M, Luo H, Wei X, Liang C, Guo G, Qiu M, Chen J, Liu Y, Li S, Li Y, Wang F, Wang F, Chi P, Zhang D. Efficacy of durvalumab plus chemotherapy in advanced biliary duct cancer and biomarkers exploration. Cancer Immunol Immunother 2024; 73:220. [PMID: 39235609 PMCID: PMC11377375 DOI: 10.1007/s00262-024-03796-1] [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: 04/07/2024] [Accepted: 08/01/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.
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Affiliation(s)
- Yunxin Lu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Yin Jin
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Furong Liu
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Zixian Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Wen Zhou
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of Molecular Diagnostics, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yang Zhang
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Bing Bai
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Yun Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Zhiqiang Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Man Nie
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Huiyan Luo
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Xiaoli Wei
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Chuqiao Liang
- Nanjing Geneseeq Technology Inc., Nanjing, 210031, Jiangsu, China
| | - Guifang Guo
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of VIP Region, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Miaozhen Qiu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Jianwen Chen
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Yu Liu
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Shengping Li
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yuhong Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Fenghua Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Feng Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China
| | - Peidong Chi
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China.
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.
| | - Dongsheng Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Kaiyang Fifth Road, Guangzhou, 510555, People's Republic of China.
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, People's Republic of China.
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15
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Huang L, Wang F, Wang F, Jiang Q, Huang J, Li X, Guo G. Anatomical classification of advanced biliary tract cancer predicts programmed cell death protein 1 blockade efficacy. Front Pharmacol 2024; 15:1375769. [PMID: 39281274 PMCID: PMC11392842 DOI: 10.3389/fphar.2024.1375769] [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: 01/29/2024] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Background Immune checkpoint blockade (ICB)-based immunotherapy has inspired new hope for advanced biliary tract cancer (BTC) treatment; however, there are no prior studies that primarily focus on different anatomical types of unresectable BTCs reacting differently to ICB. Methods We retrospectively collected data on advanced BTC patients who received anti-programmed cell death protein 1 (anti-PD1) therapy from two affiliated hospitals of Sun Yat-Sen university. The effects of anti-PD1 were compared for different anatomical sites. The GSE32225 and GSE132305 datasets were used to further analyze differences in the immune microenvironments between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). Results A total of 198 advanced BTC patients were enrolled in this study, comprising 142 patients with ICC and 56 with other cancer types ("Others" group), including ECC and gallbladder cancer. In the anti-PD1 treated patients, the ICC group (n = 90) achieved longer median progression-free survival (mPFS) (9.5 vs. 6.2 months, p = 0.02) and median overall survival (mOS) (15.1 vs. 10.7 months, p = 0.02) than the Others group (n = 26). However, chemotherapy did not show different effects between the two groups (mOS: 10.6 vs. 12.1 months, p = 0.20; mPFS: 4.9 vs. 5.7 months, p = 0.83). For the first-line anti-PD1 therapy, the ICC group (n = 70) achieved higher mOS (16.0 vs. 11.8 months, p = 0.04) than the Others group (n = 19). Moreover, most chemokines, chemokine receptors, major histocompatibility complex molecules, immunostimulators, and immunoinhibitors were stronger in ICC than ECC; furthermore, CD8+ T cells and M1 macrophages were higher in ICC than ECC for most algorithms. The immune differential genes were mainly enriched in antigen processing and presentation as well as the cytokine receptors. Conclusions This study shows that the efficacy of anti-PD1 therapy was higher in ICC than in other types of BTCs. Differences in the immune-related molecules and cells between ICC and ECC indicate that ICC could benefit more from immunotherapy.
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Affiliation(s)
- Lingli Huang
- VIP Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Fang Wang
- Department of Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Fenghua Wang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qi Jiang
- VIP Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jinsheng Huang
- VIP Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xujia Li
- VIP Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Guifang Guo
- VIP Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
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16
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Lou Y, Chen Y, Guo K, Li B, Zheng S. Emerging biomarkers for immunotherapy response in biliary tract cancers: a comprehensive review of immune checkpoint inhibitor strategies. Biomark Med 2024; 18:703-715. [PMID: 39143949 PMCID: PMC11441040 DOI: 10.1080/17520363.2024.2385297] [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: 03/19/2024] [Accepted: 07/14/2024] [Indexed: 08/16/2024] Open
Abstract
Biliary tract cancers (BTCs) have rising incidence and mortality rates. Chemotherapy's limited efficacy has led to exploring new treatments like immunotherapy. which offers modest benefits. Moreover, the identification of reliable predictive biomarkers for immune checkpoint therapy in BTCs remains elusive, hindering personalized treatment strategies. This review provides an overview of the current landscape of emerging biomarkers for immunotherapy response in BTCs. We discuss the incremental benefits of combination therapy and the evolving role of immunotherapy in managing advanced BTC. Additionally, we highlight the need for robust predictive biomarkers to optimize treatment outcomes and foster a more individualized approach to patient care. We aim to identify promising research avenues and strategies to enhance therapeutic efficacy and patient survival in BTCs.
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Affiliation(s)
- Yidan Lou
- Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, 310006, China
| | - Yijing Chen
- Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, 310006, China
| | - Kaibo Guo
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, 310006, China
- Key Laboratory of Clinical Cancer Pharmacology & Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, 310006, China
| | - Binbin Li
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, 310006, China
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Song Zheng
- Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Oncology, Hangzhou First People's Hospital, Hangzhou, 310006, China
- Key Laboratory of Clinical Cancer Pharmacology & Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, 310006, China
- Department of Oncology, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
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17
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Yue S, Zhang Y, Zhang W. Recent Advances in Immunotherapy for Advanced Biliary Tract Cancer. Curr Treat Options Oncol 2024; 25:1089-1111. [PMID: 39066855 PMCID: PMC11329538 DOI: 10.1007/s11864-024-01243-y] [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] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
OPINION STATEMENT Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC.
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Affiliation(s)
- Shiwei Yue
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Yunpu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato‑Pancreatic‑Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, 1095 Jiefang Avenue, 430030, Wuhan, China.
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18
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Storandt MH, Jin Z, Mahipal A. Evaluating the Therapeutic Potential of Durvalumab in Adults with Locally Advanced or Metastatic Biliary Tract Cancer: Evidence to Date. Onco Targets Ther 2024; 17:383-394. [PMID: 38774819 PMCID: PMC11107832 DOI: 10.2147/ott.s391707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 05/06/2024] [Indexed: 05/24/2024] Open
Abstract
Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC.
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Affiliation(s)
| | - Zhaohui Jin
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
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19
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Zhang Y, Zuo C, Li Y, Liu L, Yang B, Xia J, Cui J, Xu K, Wu X, Gong W, Liu Y. Single-cell characterization of infiltrating T cells identifies novel targets for gallbladder cancer immunotherapy. Cancer Lett 2024; 586:216675. [PMID: 38280478 DOI: 10.1016/j.canlet.2024.216675] [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: 11/16/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024]
Abstract
Gallbladder cancer (GBC) is among the most common malignancies of biliary tract system due to its limited treatments. The immunotherapeutic targets for T cells are appealing, however, heterogeneity of T cells hinds its further development. We systematically construct T cell atlas by single-cell RNA sequencing; and utilized the identified gene signatures of high_CNV_T cells to predict molecular subtyping towards personalized therapeutic treatments for GBC. We identified 12 T cell subtypes, where exhausted CD8+ T cells, activated/exhausted CD8+ T cells, and regulatory T cells were predominant in tumors. There appeared to be an inverse relationship between Th17 and Treg populations with Th17 levels significantly reduced, whereas Tregs were concomitantly increased. Furthermore, we first established subtyping criterion to identify three subtypes of GBC based on their pro-tumorigenic microenvironments, e.g., the type 1 group shows more M2 macrophages infiltration, while the type 2 group is infiltrated by highly exhausted CD8+ T cells, B cells and Tregs with suppressive activities. Our study provides valuable insights into T cell heterogeneity and suggests that molecular subtyping based on T cells might provide a potential immunotherapeutic strategy to improve GBC treatment.
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Affiliation(s)
- Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Chunman Zuo
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China; Key Laboratory of Symbolic Computation and knowledge Engineering of Ministry of Education, Jilin University, Changchun, 130022, China.
| | - Yang Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Liguo Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Bo Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Junjie Xia
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China
| | - Jiangnan Cui
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China
| | - Keren Xu
- CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xiangsong Wu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
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20
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Zhao P, Jin R, Zhao B, Han L, Chen W, Hao N, Cui Y, Madan A, Awosika J, Lloyd S, Zhang Y. The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review. J Gastrointest Oncol 2024; 15:514-528. [PMID: 38482240 PMCID: PMC10932650 DOI: 10.21037/jgo-23-843] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/01/2024] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer. METHODS The literature on ICI treatment in GI cancers was searched in the PubMed, Embase, and Cochrane Library databases for publications up to April 2023. KEY CONTENT AND FINDINGS Clinical practice and research has gradually revealed some biomarkers related to the treatment of GI cancers with ICIs, which can be roughly divided into three types: biomarkers that predict the effectiveness of ICIs treatment, biomarkers associated with resistance to ICIs, and biomarkers associated with immune related adverse events (irAEs). This review article provides a literature review on biomarkers related to the efficacy of ICIs in the treatment of GI cancers. CONCLUSIONS According to existing clinical research results, there are multiple biomarkers that can be used for predicting and monitoring the efficacy and risk of adverse events of ICIs in the treatment of digestive system malignant tumors.
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Affiliation(s)
- Peixi Zhao
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Rui Jin
- Department of Clinical Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Bin Zhao
- Department of Research and Teaching, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Le Han
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenjuan Chen
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Nina Hao
- Department of Research and Teaching, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Cui
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ankit Madan
- Medstar Southern Maryland Hospital Center, Clinton, MD, USA
| | - Joy Awosika
- National Institutes of Health, National Cancer Institute, Bethesda, MD, USA
| | - Shane Lloyd
- Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT, USA
| | - Yili Zhang
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
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21
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Cheng Y, Bu D, Zhang Q, Sun R, Lyle S, Zhao G, Dong L, Li H, Zhao Y, Yu J, Hao X. Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer. J Adv Res 2023; 51:121-134. [PMID: 36351537 PMCID: PMC10491970 DOI: 10.1016/j.jare.2022.10.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 11/07/2022] Open
Abstract
INTRODUCTION Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood. OBJECTIVES This study aims to evaluate the prognostic value of TMB in Chinese GC and further classify TMB-high GC (GCTMB-H) patients combing with mutational signatures. METHODS Genomic profiling of 435 cancer-gene panel was performed using 206 GC samples from Chinese people. Actionable genetic alterations were compared across all the samples to generate actionable subtyping. The prognostic value of TMB in Chinese GC was evaluated. Mutational signatures were analyzed on TMB-H subtype to stratify the prognosis of TMB. Transcriptomic analysis was applied to compare the distributed immunocytes among different subtypes. RESULTS 88.3% (182/206) of GC samples had at least one mutation, while 45.1% (93/206) had at least one somatic copy number alteration (SCNA). 29.6% (61/206) of GC samples were TMB-H, including 13 MSI-H and 48 MSS tumors. According to distinct genetic alteration profiles of 69 actionable genes, we classified GC samples into eight molecular subtypes, including TMB-H, ERBB2 amplified, ATM mutated, BRCA2 mutated, CDKN2A/B deleted, PI3KCA mutated, KRAS mutated, and less-mutated subtype. TMB-H subtype presented a remarkable immune-activated phenotype as determined by transcriptomic analysis that was further validated in the TCGA GC cohort. GCTMB-H patients exhibited significantly better survival (P = 0.047). But Signature 1-high GCTMB-H patients had relatively worse prognosis (P = 0.0209, HR = 2.571) than Signature 1-low GCTMB-H patients from Chinese GC cohort, also validated in TCGA GC cohort, presenting highly activated carbohydrate, fatty acid or lipid metabolism. CONCLUSION The Signature 1-high GCTMB-H could be a marker of poor prognosis and is associated with metabolism disorder.
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Affiliation(s)
- Yanan Cheng
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Dechao Bu
- Research Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Qiaoling Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Rebecca Sun
- KEW, Inc., 303 Wyman Street, Waltham, MA, USA
| | | | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Li Dong
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yi Zhao
- Research Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China.
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Xishan Hao
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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22
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Kuniyoshi N, Imazu H, Masuzaki R, Yamazaki M, Hamana S, Nomura S, Hayama J, Osawa R, Yamada K, Fujisawa M, Saito K, Kogure H. Diagnostic utility of quantitative analysis of microRNA in bile samples obtained during endoscopic retrograde cholangiopancreatography for malignant biliary strictures. PLoS One 2023; 18:e0289537. [PMID: 37561751 PMCID: PMC10414614 DOI: 10.1371/journal.pone.0289537] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/20/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND The sensitivity of bile cytology for malignant biliary strictures is not adequate. To overcome this limitation, we evaluated whether quantitative analysis of microRNAs (miRNAs) in bile can provide a precise diagnosis of malignant biliary strictures due to pancreatic cancer (PC) and biliary tract cancer (BTC). METHODS This was a retrospective evaluation of miRNA levels in stored bile samples of patients with PC, BTC or benign biliary stricture obtained during biliary drainage from April 2019 to December 2021 at our institution. A total of 113 patients (PC; n = 40, BTC; n = 38, control; n = 35) were enrolled. The miRNA candidates to be quantified were determined with microarray analysis from each 3 patients with PC, BTC and controls. RESULTS Using microarray analysis, we confirmed four significantly up-regulated miRNAs (miR-1275, miR-6891-5p, miR-7107-5p, miR-3197) in patients with PC and BTC compared to control patients. Quantitative PCR was then performed in 113 bile samples for these miRNAs. miR-1275 was significantly upregulated in PC (p = 0.003) and BTC (p = 0.049) compared to controls, miR-6891-5p was significantly upregulated in PC compared to controls (p = 0.025). In particular, a combination of bile cytology and miR-1275 in bile showed a sensitivity of 77.5% (95% CI, 70.7-77.5%), specificity of 100% (95% CI, 92.2-100%) and an area under the curve (AUC) of 0.93, and provided a significantly greater additional diagnostic effect than bile cytology alone (p = 0.014). CONCLUSIONS This study suggest that bile miRNAs could be potential biomarkers for pancreato-biliary diseases, particularly miR-1275 and miR-6891-5p may be helpful in the diagnosis of PC and BTC.
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Affiliation(s)
- Noriyuki Kuniyoshi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Suguru Hamana
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shuzo Nomura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Jo Hayama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Rota Osawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Koji Yamada
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Chiyoda-ku, Tokyo, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Kei Saito
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Hirofumi Kogure
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
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Peng J, Fang S, Li M, Liu Y, Liang X, Li Z, Chen G, Peng L, Chen N, Liu L, Xu X, Dai W. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis. Open Life Sci 2023; 18:20220652. [PMID: 37483430 PMCID: PMC10358752 DOI: 10.1515/biol-2022-0652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/13/2023] [Accepted: 06/05/2023] [Indexed: 07/25/2023] Open
Abstract
The aim of this study is to investigate certain genetic features of intrahepatic cholangiocarcinoma (ICCA). A total of 12 eligible ICCA patients were enrolled, and tumor tissues from the patients were subjected to next-generation sequencing of a multi-genes panel. Tumor mutation burden (TMB), mutated genes, copy number variants (CNVs), and pathway enrichment analysis were performed. The median TMB was 2.76 Mutation/Mb (range, 0-36.62 Mutation/Mb) in ICCA patients. The top two most commonly mutated genes in ICCA were KRAS (33%) and TP53 (25%). The co-mutations of KRAS and TP53 were 16.7% (2/12) in ICCA patients. Notably, patient P6 with the highest TMB did not have KRAS and TP53 mutations. Additionally, TP53 and/or KRAS alterations were significantly associated with poor progression-free survival than those with wild type (1.4 months vs 18 months). DNA damage repair and homologs recombinant repair deficiencies were significantly associated with high TMB in ICCA cases. In conclusion, we found that certain genetic mutations of TP53 and KRAS could predict poor prognosis in ICCA patients.
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Affiliation(s)
- Jianbo Peng
- Foshan Traditional Chinese Medicine Hospital, Guangdong, 518000, China
| | - Shuo Fang
- Department of Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518000, China
| | - Meisheng Li
- Foshan First People’s Hospital, Guangdong, 518000, China
| | - Yuxin Liu
- Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Xiaolu Liang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Zuobiao Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Gaohui Chen
- Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Lijiao Peng
- Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Nianping Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Lei Liu
- Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Xiaohong Xu
- Department of Ultrasound, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
| | - Wei Dai
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, China
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Zhang Z, Wang D, Yang L, Zhao L, Yang L, Zhang J, Lou C. Efficacy and safety analysis of chemotherapy combined with immunotherapy compared with standard chemotherapy for advanced biliary tract malignant tumors. Cancer Med 2023; 12:15217-15228. [PMID: 37392168 PMCID: PMC10417155 DOI: 10.1002/cam4.6209] [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: 07/16/2022] [Revised: 04/08/2023] [Accepted: 04/15/2023] [Indexed: 07/03/2023] Open
Abstract
OBJECTIVE The treatment of biliary tract (BTC) cancer remains relatively limited, especially in the setting of advanced BTC. Immune checkpoint inhibitors (ICIs) have shown some effects in a variety of solid tumors, but their efficacy and safety in patients with advanced BTC are still elusive, which require in-depth analysis. METHODS The clinical information of 129 patients diagnosed with advanced BTC between 2018 and 2021 were retrospectively reviewed. All patients were treated with chemotherapy, while a portion of them (64 patients) were treated with ICIs, the other 64 patients were not. Therefore, we divided the patients into two groups, SC (standard chemotherapy) and CI (chemotherapy in combined with immunotherapy), then we analyzed the benefit of adding ICIs according to efficacy, adverse events, progression-free survival (PFS), progressive disease (PD), and the influence of various factors and effectiveness. RESULTS The mean PFS was 9.67 months for CI group and 6.83 months for SC group. The PFS was prolonged by 2.84 months with ICI addition, and the difference was statistically significant (t = 3.114, 95% CI: 1.06-4.74, p < 0.001). The objective response rate (ORR) was 32.81% (21/64) for the CI group versus 10.77% (7/65) for the SC group, and the disease control rate (DCR) was 79.69% (51/64) versus 67.69% (44/65), respectively. Regression analysis showed that factors such as changes in CA19-9, the level of PD-L1 expression, tobacco and alcohol, and the neutrophil-lymphocyte (NLR) ratio all influenced PFS (p < 0.05 for all these factors). For the treatment-related adverse events (TRAEs), the highest grade 3-4 adverse effects were thrombocytopenia in 7.75% (10/129) and neutropenia in 3.1% (4/129), immune-related adverse events (irAEs) occurred in 32.8% (21/64), and all were grade 1-2. CONCLUSIONS Our results showed that ICIs combined with chemotherapy exhibited good antitumor activity with acceptable safety and could be recommended as first-line treatment for patients with advanced BTC.
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Affiliation(s)
- Zhengfeng Zhang
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
| | - Dazhen Wang
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
| | - Liu Yang
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
| | - Lu Zhao
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
| | - Lei Yang
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
| | | | - Changjie Lou
- Department of GastroenterologyHarbin Medical University Cancer HospitalHarbinChina
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25
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Greten TF, Schwabe R, Bardeesy N, Ma L, Goyal L, Kelley RK, Wang XW. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2023; 20:349-365. [PMID: 36697706 DOI: 10.1038/s41575-022-00741-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2022] [Indexed: 01/27/2023]
Abstract
Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Liver Cancer Program, Bethesda, MD, USA.
| | - Robert Schwabe
- Institute of Human Nutrition, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University, New York, NY, USA
| | - Nabeel Bardeesy
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lipika Goyal
- Division of Oncology, Stanford School of Medicine, Palo Alto, CA, USA
| | - Robin K Kelley
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Xin W Wang
- Liver Cancer Program, Bethesda, MD, USA
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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Zhou Y, Yuan K, Yang Y, Ji Z, Zhou D, Ouyang J, Wang Z, Wang F, Liu C, Li Q, Zhang Q, Li Q, Shan X, Zhou J. Gallbladder cancer: current and future treatment options. Front Pharmacol 2023; 14:1183619. [PMID: 37251319 PMCID: PMC10213899 DOI: 10.3389/fphar.2023.1183619] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 04/28/2023] [Indexed: 05/31/2023] Open
Abstract
Surgery remains the preferred treatment option for early-stage gallbladder cancer (GBC). According to the anatomical position of the primary tumor, accurate preoperative stage and strict control of surgical indications, appropriate surgical strategies are selected to achieve the optimal surgical effect. However, most patients have already been at the locally advanced stage or the tumor has metastasized at the initial diagnosis. The postoperative recurrence rate and 5-year survival rate remain unsatisfactory even after radical resection for gallbladder cancer. Hence, there is an urgent need for more treatment options, such as neoadjuvant therapy, postoperative adjuvant therapy and first-line and second-line treatments of local progression and metastasis, in the whole-course treatment management of gallbladder cancer patients. In recent years, the application of molecular targeted drugs and immunotherapy has brought greater hope and broader prospects for the treatment of gallbladder cancer, but their effects in improving the prognosis of patients still lack sufficient evidence-based medicine evidence, so many problems should be addressed by further research. Based on the latest progress in gallbladder cancer research, this review systematically analyzes the treatment trends of gallbladder cancer.
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Affiliation(s)
- Yanzhao Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Department of Hepatobiliary Cancer, Liver Cancer Research Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kun Yuan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yi Yang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zemin Ji
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Dezheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jingzhong Ouyang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Zhengzheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Fuqiang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Chang Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Qingjun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Qi Zhang
- Department of Hepatobiliary Cancer, Liver Cancer Research Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Qiang Li
- Department of Hepatobiliary Cancer, Liver Cancer Research Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiao Shan
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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27
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Qin BD, Jiao XD, Wang Z, Liu K, Wu Y, Ling Y, Chen SQ, Zhong X, Duan XP, Qin WX, Xue L, Guo ZH, Zang YS. Pan-cancer efficacy and safety of anlotinib plus PD-1 inhibitor in refractory solid tumor: A single-arm, open-label, phase II trial. Int J Cancer 2023. [PMID: 37155342 DOI: 10.1002/ijc.34546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/24/2023] [Accepted: 04/05/2023] [Indexed: 05/10/2023]
Abstract
The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD-1 inhibitor to treat refractory solid tumor. APICAL-RST is an investigator-initiated, open-label, single-arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD-1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression-free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty-one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention-to-treat cohort, and 24.3% and 81.1% in the efficacy-evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%-77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23-24.4), and the 12- and 36-month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty-one (75.6%) patients experienced at least one treatment-related adverse event. The most common adverse events were hypothyroidism, hand-foot syndrome and malaise. This phase II trial showed that anlotinib plus PD-1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor.
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Affiliation(s)
- Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhan Wang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ying Wu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yan Ling
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Shi-Qi Chen
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xue Zhong
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Peng Duan
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wen-Xing Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lei Xue
- Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhen-Hong Guo
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
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Beri N. Immune checkpoint inhibitors in cholangiocarcinoma. Immunotherapy 2023; 15:541-551. [PMID: 37096964 DOI: 10.2217/imt-2022-0288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
Cholangiocarcinoma is an epithelial malignancy originating in the biliary tracts and frequently recurs even with surgical resection. Unresectable disease has a 5-year overall survival of less than 10%. Given this poor prognosis, additional therapies are urgently needed. Chemotherapy has been the mainstay of treatment for many years. However, with the incorporation of immunotherapy into the treatment of other malignancies, there has been a great deal of interest in immunotherapy for biliary cancers. Recently, durvalumab was approved in combination with gemcitabine and cisplatin for the treatment of unresectable cholangiocarcinoma in the first-line setting. However, predicting which patients may respond to immunotherapy remains a challenge due to the lack of a reliable biomarker.
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Affiliation(s)
- Nina Beri
- Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA
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29
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Wang Y, Xiao X, Li Y. Construction and validation of a cuproptosis-related lncRNA signature for the prediction of the prognosis of LUAD and LUSC. Sci Rep 2023; 13:2477. [PMID: 36774418 PMCID: PMC9922262 DOI: 10.1038/s41598-023-29719-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 02/09/2023] [Indexed: 02/13/2023] Open
Abstract
Lung cancer is one of the most prevalent malignant tumors worldwide, with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) accounting for the majority of cases. Cuproptosis, tumor immune microenvironment (TIME) and long non-coding RNA (lncRNA) have been demonstrated to be associated with tumorigenesis. The objective of the present study was to develop a novel cuproptosis-related lncRNA signature to assess the association between cuproptosis and TIME in patients with LUAD or LUSC and to predict prognosis. Based on the outputs of the least absolute shrinkage and selection operator regression model, a cuproptosis-related lncRNA signature was developed. Kaplan-Meier survival curves were generated to confirm the predictive ability of the signature. Univariate and multivariate analysis was also performed to determine the association between overall survival and this signature and other clinical characteristics, and a nomogram was created. Additionally, the relationship between the signature, TIME, tumor mutation burden and m6A methylation was established. The results of the present study revealed that 8 cuproptosis-related lncRNAs were associated with the prognosis of patients with LUAD and LUSC. This novel cuproptosis-related lncRNA signature is associated with TIME and m6A methylation in LUAD and LUSC and can predict prognosis with accuracy.
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Affiliation(s)
- Yu Wang
- Department of Cardiology, Shenzhen Qianhai Taikang Hospital, Shenzhen, China
- Department of Esophageal surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xu Xiao
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yan Li
- Department of Cardiology, Shenzhen Qianhai Taikang Hospital, Shenzhen, China.
- Department of Cardiology, Peking University Shenzhen Hospital, Shenzhen, China.
- Department of Cardiology, Shenzhen Qianhai Taikang Hospital, No. 63 Qianwan Road 1, Shenzhen, 518054, Guangdong, China.
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30
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Testa U, Pelosi E, Castelli G. The clinical value of identifying genetic abnormalities that can be targeted in cholangiocarcinomas. Expert Rev Anticancer Ther 2023; 23:147-162. [PMID: 36654529 DOI: 10.1080/14737140.2023.2170878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Cholangiocarcinomas (CCAs) are a heterogenous group of epithelial malignancies originating at any level of the biliary tree and are subdivided according to their location into intrahepatic (iCCA) and extrahepatic (eCCA). AREAS COVERED This review provides an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. EXPERT OPINION With the development of genetic sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches, including FGFR2, IDH1, BRAF, NTRK, HER2, ROS, and RET. Furthermore, identification of the cellular and molecular structure of the tumor microenvironment has contributed to the development of novel therapies, such as tumor immunotherapy. Combination therapies of chemotherapy plus targeted molecules or immunotherapy are under evaluation and offer the unique opportunity to improve the outcomes of CCA patients with advanced disease.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Superiore Di Sanità, Rome, Italy
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31
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Jin Z, Liu Y. Identification of Novel m6A-Related Long Non-Coding RNA Signatures for Cholangiocarcinoma Using Integrated Bioinformatics Analyses. J Biomed Nanotechnol 2022. [DOI: 10.1166/jbn.2022.3471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
Abstract
Traditional methods used to treat cholangiocarcinoma are less effective, and the identification of new CHOL signature genes can help in the early clinical diagnosis and intervention of cholangiocarcinoma. In this work, we used integrated bioinformatics analysis to find new m6a-associated
lncRNA signatures in cholangiocarcinoma. Pearson correlation test was used to identify m6A-lncRNAs by co-expression analysis of m6A-mrna and lncRNAs. we then selected m6A-lncRNAs co-expressed with METTL3 and METTL14 genes and screened for DEm6A-lncRNAs by comparing expression differences.
we then used R package of Spearman coefficient correlation analysis to investigate the relevance of m6A-lncrna expression in CHOL. To determine the relative levels of immune cell infiltration, we performed ssGSEA analysis on all samples using the R package, and then we used graphs to illustrate
the differences in immune cell infiltration between the CHOL and NC groups. The results of this study will help to identify new CHOL-causing biosignatures, which are important for the early clinical detection and management of CHOL.
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32
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Zeng TM, Pan YF, Yuan ZG, Chen DS, Song YJ, Gao Y. Immune-related RNA signature predicts outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma. Front Immunol 2022; 13:943066. [PMID: 36159865 PMCID: PMC9501891 DOI: 10.3389/fimmu.2022.943066] [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: 05/13/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundImmune checkpoint inhibitor (ICI)-combined chemotherapy in advanced intrahepatic cholangiocarcinoma has been proved to have more efficacy in a series of clinical trials. However, whether the tumor microenvironment (TME) plays a vital role in immune-combined therapy has not been rigorously evaluated.MethodsFirstly, we assayed the immunogenic properties of GEM-based chemotherapy. Then, 12 ICC patients treated with PD-1 inhibitor (sintilimab) combined with gemcitabine and cisplatin (GemCis) from a phase 2 clinical trial (ChiCTR2000036652) were included and their immune-related gene expression profiles were analyzed using RNA from baseline tumor samples. Immune-related signature correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in an ICC cohort with 26 patients. Multiplexed immunofluorescence (mIF) and flow cytometry (FCM) analysis were performed to evaluate the immune-related molecules with therapeutic outcomes.ResultsGEM-based chemotherapy induced immunogenic cell death of cholangiocarcinoma cells, together with increased CD274 expression. In an ICC cohort, we found that upregulation of immune-checkpoint molecules and immune response-related pathways were significantly related to better clinical outcome. On the contrary, baseline immune-cell proportions in tumor tissues did not show any correlation with clinical benefit between responders and non-responders. Immune-related signature (including six genes) correlating with clinical outcome was identified according to the 12 ICC patients, and its predictive value was validated in a small ICC cohort with 26 patients.ConclusionImmune-related RNA signature predicts the outcome of PD-1 inhibitor-combined GEMCIS therapy in advanced intrahepatic cholangiocarcinoma, which could be tested as a biomarker for immune-chemotherapy in the future.
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Affiliation(s)
- Tian-mei Zeng
- School of Medicine, Tongji University, Shanghai, China
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yu-fei Pan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zhen-gang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Dong-sheng Chen
- Jiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, China
| | - Yun-jie Song
- Jiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, China
| | - Yong Gao
- School of Medicine, Tongji University, Shanghai, China
- Department of Oncology, Shanghai East Hospital, Shanghai, China
- *Correspondence: Yong Gao,
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Yu H, Xu Y, Gao W, Li M, He J, Deng X, Xing W. Comprehensive germline and somatic genomic profiles of Chinese patients with biliary tract cancer. Front Oncol 2022; 12:930611. [PMID: 36072793 PMCID: PMC9441936 DOI: 10.3389/fonc.2022.930611] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Biliary tract cancer (BTC) is an uncommon but highly lethal malignancy with poor clinical outcomes. To promote the development of precision medicine for BTC, uncovering its genomic profile becomes particularly important. However, studies on the genomic feature of Chinese BTC patients remain insufficient. METHODS A total of 382 Chinese patients with BTC were enrolled in this study, including 71 with intrahepatic cholangiocarcinoma (ICC), 194 with extrahepatic cholangiocarcinoma (ECC), and 117 with gallbladder carcinoma (GBC). Genetic testing was performed by utilizing the next-generation sequencing (NGS) of 499 cancer-related genes and the results were compared to those of Western BTC patients (MSKCC cohorts). RESULTS The most prevalent genes were TP53 (51.6%), ARID1A (25.9%), KMT2C (24.6%), NCOR1 (17%), SMAD4 (15.2%), KRAS (14.9%), KMT2D (14.9%), ATM (14.1%), and APC (13.9%) in Chinese BTC patients. TP53, SMAD4, and APC were more prevalent in GBC, ECC, and ICC, respectively. In addition, 10.5% of Chinese BTC patients harbored pathogenic or likely pathogenic (P/LP) germline alterations in 41 genes, which were mainly related to DNA damage repair (DDR). Additionally, the genomic features of Chinese and Western BTC tumors were similar, with the exception of the notable difference in the prevalence of TP53, KRAS, IDH1, KMT2C, and SMAD4. Notably, Chinese BTC patients had high prevalence (57.1%) of actionable alterations, especially for those with ECC, and half (192/382) of them had somatic DDR alterations, with the prevalence of deleterious ones being significantly higher than their Western counterparts. Twenty-three percent of patients had a higher tumor mutational burden (TMB-H, over 10 mutations/MB), and TMB was significantly higher in those with deleterious DDR alterations and/or microsatellite instability-high. The most common mutational signature in BTC patients was Signature 1, and interestingly, Signatures 1, 4, and 26 were significantly associated with higher TMB level, but not with the survival of patients who had received immunotherapy in pan-cancer. CONCLUSION Our study elaborated the distinct germline and somatic genomic characteristics of Chinese BTC patients and identified clinically actionable alterations, highlighting the possibility for the development and application of precision medicine.
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Affiliation(s)
- Haipeng Yu
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Yan Xu
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Wei Gao
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mei Li
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Ji’an He
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xiaoqian Deng
- Department of Medical Affairs, Lifehealthcare Clinical Laboratory, Hangzhou, China
| | - Wenge Xing
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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Chen R, Zheng D, Li Q, Xu S, Ye C, Jiang Q, Yan F, Jia Y, Zhang X, Ruan J. Immunotherapy of cholangiocarcinoma: Therapeutic strategies and predictive biomarkers. Cancer Lett 2022; 546:215853. [DOI: 10.1016/j.canlet.2022.215853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/02/2022]
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Zhang S, Xiao X, Wang Y, Song T, Li C, Bao H, Liu Q, Sun G, Sun X, Su T, Fu T, Wang Y, Liang P. Developing an Immune-Related Signature for Predicting Survival Rate and the Response to Immune Checkpoint Inhibitors in Patients With Glioma. Front Genet 2022; 13:899125. [PMID: 35719378 PMCID: PMC9204856 DOI: 10.3389/fgene.2022.899125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Glioma is one of the most aggressive cancer types affecting the central nerve system, with poor overall survival (OS) rates. The present study aimed to construct a novel immune-related signature to predict prognosis and the efficiency of immunotherapy in patients with glioma.Methods: The mRNA expression data and other clinical information of patients with glioblastoma multiforme (GBM) and low grade glioma (LGG) were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. The immune-related genes were obtained from the Immunology Database and Analysis Portal database. Subsequently, an immune-related signature was created following the results obtained from the Least Absolute Shrinkage and Selection Operator regression model. To validate the predictability of the signature, Kaplan-Meier survival curves and time-dependent receiver operating characteristic curves were created. Moreover, both univariate and multivariate analyses were carried out using the OS between this signature and other clinicopathologic factors, and a nomogram was constructed. In addition, the association between signature, immune cell infiltration, tumor mutation burden and immunophenoscore were determined.Results: Results of the present study using 118 GBM and LGG samples uncovered 15 immune-related genes that were also differently expressed in glioma samples. These were subsequently used to construct the immune-related signature. This signature exhibits the ability to predict prognosis, the infiltration of immune cells in the tumor microenvironment and the response of patients with glioma to immunotherapy.Conclusion: Results of the present study demonstrated that the aforementioned novel immune-related signature may accurately predict prognosis and the response of patients with glioma to immunotherapy.
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Affiliation(s)
- Sibin Zhang
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xu Xiao
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yu Wang
- Department of Esophageal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tianjun Song
- Department of Medicine II, University Hospital LMU Munich, Munich, Germany
| | - Chenlong Li
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongbo Bao
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qing Liu
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Guiyin Sun
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaoyang Sun
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tianqi Su
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Tianjiao Fu
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yujie Wang
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Peng Liang
- Department of Neurosurgery, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Peng Liang,
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Guo C, Liu Z, Yu Y, Chen Y, Liu H, Guo Y, Peng Z, Cai G, Hua Z, Han X, Li Z. TP53 /KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma. Front Genet 2022; 13:844800. [PMID: 35401671 PMCID: PMC8990229 DOI: 10.3389/fgene.2022.844800] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/07/2022] [Indexed: 11/28/2022] Open
Abstract
Background: Due to high invasiveness and heterogeneity, the morbidity and mortality of intrahepatic cholangiocarcinoma (ICC) remain unsatisfied. Recently, the exploration of genomic variants has decoded the underlying mechanisms of initiation and progression for multiple tumors, while has not been fully investigated in ICC. Methods: We comprehensively analyzed 899 clinical and somatic mutation data of ICC patients from three large-scale cohorts. Based on the mutation landscape, we identified the common high-frequency mutation genes (FMGs). Subsequently, the clinical features, prognosis, tumor mutation burden (TMB), and pharmacological landscape from patients with different mutation carriers were further analyzed. Results: We found TP53 and KRAS were the common FMGs in the three cohorts. Kaplan–Meier survival curves and univariate and multivariate analysis displayed that TP53 and KRAS mutations were associated with poor prognosis. Considering the co-mutation phenomenon of TP53 and KRAS, we stratified patients into “Double-WT,” “Single-Hit,” and “Double-Hit” phenotypes by mutation status. Patients with the three phenotypes showed significant differences in the mutation landscape. Additionally, compared with “Double-WT” and “Single-Hit” phenotypes, patients with “Double-Hit” presented a dismal prognosis and significantly high TMB. Through chemotherapy sensitivity analysis, we identified a total of 30 sensitive drugs for ICC patients, of which 22 were drugs sensitive to “Double-WT,” 7 were drugs sensitive to “Double-Hit,” and only one was a drug sensitive to “Single-Hit.” Conclusion: Our study defined a novel mutation classification based on the common FMGs, which may contribute to the individualized treatment and management of ICC patients.
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Affiliation(s)
- Chunguang Guo
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yin Yu
- Department of Pathophysiology, School of Basic Medical Sciences, The Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Yunfang Chen
- Department of Oncology, Zhumadian Central Hospital Affiliated to Huanghuai University, Zhumadian, China
| | - Hui Liu
- Department of Nursing, Zhumadian Central Hospital Affiliated to Huanghuai University, Zhumadian, China
| | - Yaming Guo
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenyu Peng
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Gaopo Cai
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhaohui Hua
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Zhaohui Hua, ; Xinwei Han, ; Zhen Li,
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Zhaohui Hua, ; Xinwei Han, ; Zhen Li,
| | - Zhen Li
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Zhaohui Hua, ; Xinwei Han, ; Zhen Li,
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Brown ZJ, Hewitt DB, Pawlik TM. Biomarkers of intrahepatic cholangiocarcinoma: diagnosis and response to therapy. FRONT BIOSCI-LANDMRK 2022; 27:85. [PMID: 35345317 DOI: 10.31083/j.fbl2703085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 01/03/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.
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Affiliation(s)
- Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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